Dissertations / Theses: 'Melanoma – Immunotherapy'

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Woods, David Michael. "Histone Deacetylases as Targets for Melanoma Immunotherapy." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4856.

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Cancer represents the second leading cause of death in the United States. For many malignancies, currently available treatment options offer little long-lasting survival benefits to patients. However, recent studies have shown immunotherapeutic approaches to be an attractive strategy to cancer treatment. While many current immunotherapeutic strategies convey durable responses, such responses are only seen in a minority of patients. An increased understanding of the mechanisms governing tumor immunogenicity and the biology of immune responses is crucial to improving upon the efficacy of current and future cancer immunotherapies. Histone deacetylases (HDACs), enzymes classically associated with regulation of gene expression, have been therapeutic targets in various cancers for several years due to their involvement in cell growth. However, it has become increasingly clear that HDACs are intimately involved in regulating both the immunogenicity of tumor cells and immune response of leukocytes and lymphocytes. In order to expand upon this growing knowledge, the therapeutic efficacy of the pan-HDAC inhibitor LBH589 in the treatment of melanoma was studied. The results presented here demonstrate that LBH589 is a potent inhibitor of growth in a wide variety of melanomas through induction of cell cycle arrest and apoptosis. Additionally, LBH589 increases the immune visibility of melanoma cells by increasing expression of several immune associated cell surface markers (e.g. MHC I, MHC II, CD80, CD86) in addition to upregulating expression of melanoma differentiation antigens. Furthermore, LBH589 treatment of immune cells results in an enhanced pro-inflammatory phenotype of both APCs and T-cells. These combined effects result in better activation of T-cells and ultimately prolonged survival in LBH589 treated, melanoma-baring mice. To further the understanding of the role of individual HDACs in the T-cell response, the biology of the newest HDAC, HDAC11, was further assessed. To this end, it is shown that HDAC11 is differentially expressed in T-cell populations, and expression is rapidly decreased following activation. Utilizing an HDAC11 knockout (HDAC11KO) mouse strain, it is found that both CD4+ and CD8+ T-cells lacking HDAC11 have an enhanced type 1 effector function characterized by increased proliferation and secretion of IL-2, TNF and IFN-γ. Additionally, HDAC11KO CD8+ T-cells have increased expression of both granzyme B and perforin. HDAC11KO T-cells also demonstrate enhanced resistance to inhibition by Tregs and anergy formation. As a possible mechanism for the observed phenotype, it is also demonstrated that HDAC11KO T-cells produce elevated levels of the transcription factors Eomes and T-bet, both at the basal state and post-activation. In vivo, T-cells lacking HDAC11 have a more potent and robust ability to cause GvHD and mediate an enhanced anti-tumor response. Collectively, these results demonstrate that targeting of HDACs is a viable approach to cancer immunotherapy, and that targeting of specific HDACs may be an attractive strategy for optimizing immunotherapy efficacy while minimizing side effects.

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Barnard, Amanda Louise. "A murine model for immunotherapy of melanoma." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298460.

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Lo, Jennifer Alys. "Regulation of the Inflamed Tumor Phenotype in Melanoma Immunotherapy." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493467.

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Immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) pathways can deliver durable anti-tumor effects. However, a major fraction of metastatic cancer patients fail to respond to checkpoint blockade. Recent studies suggest that efficacy of checkpoint inhibitors is associated with inflammation in the tumor microenvironment. In this thesis, I demonstrate using genetically-defined murine models that sterile melanomas can be converted into inflamed tumors with improved responses to checkpoint blockade via two independent approaches: introduction of neoantigens and a novel combinatorial therapeutic strategy. In addition to tumor inflammation, genomic studies have identified elevated numbers of neoantigens, mutated proteins that can serve as targets of immune responses, as potential predictors of clinical benefit. The preponderance of UVR-associated somatic mutations in melanoma has been proposed to play a role in mediating responses to immunotherapy, but model systems to study the contribution of such mutations to anti-melanoma immunity have been lacking. In chapter 2, I present a BrafV600E/Pten-/- syngeneic tumor graft murine model in which melanomas bearing numerous non-synonymous UVB-induced mutations were markedly more inflamed and responsive to PD-1 inhibition than matched parental melanomas. For the treatment of neoantigen-deficient, poorly-inflamed tumors, in chapter 3 I tested the novel combination of imiquimod, ablative fractional photothermolysis (aFP), and checkpoint inhibitors. In anti-PD-1 resistant models of melanoma and pancreatic adenocarcinoma, addition of imiquimod and aFP produced abscopal tumor regressions with long-term survival in 50-60% of cases. Combination therapy stimulated autoimmunity against wildtype tumor-lineage antigens, suggesting that therapeutic strategies which enhance inflammation and responses against self-antigens may bypass a need for neoantigens and produce major regressions of cancers that are currently refractory to checkpoint blockade in the clinic. In chapter 4 I show that PD-L1 expression is transcriptionally regulated by the melanocyte lineage factor and oncogene microphthalmia-associated transcription factor (MITF). PD-L1 expression is significantly correlated with MITF copy number in patient melanomas and is induced in skin as part of the MITF-dependent tanning response pathway. Our data suggest that loss of PD-L1 predisposes mice to apparent vitiligo after chronic UVR, suggesting that the UVR-MITF-PD-L1 axis represents a melanocyte lineage-specific mechanism of immune tolerance.
Medical Sciences

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Thomas, Myles Duncan. "Production and characterisation of novel human monoclonal antibodies against malignant melanoma." Thesis, University of East London, 1995. http://roar.uel.ac.uk/1275/.

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Malignant melanoma is an immunogenic tumour capable of inducing a humoral immune response, as shown by tumour-reactive serum antibody in patients. Lack of effective chemotherapy in association with the immunogenic nature of the malignancy, has stimulated interest in the immunological management of the malignancy by antibody. Many mouse monoclonal antibodies against melanoma antigens have been developed, and some have been shown to induce tumour regression. However, a limitation on the use of mouse monoclonal antibodies in patients is the induction of an immune response against the immunising xenogeneic protein. The employment of human monoclonal antibodies, may be expected to reduce the patient's immune response against the allogeneic protein. Although more difficult to produce than mouse monoclonal antibodies, several human monoclonal antibodies have been established which induce tumour regression. Here I describe the establishment of mouse/human heterohybridomas producing human monoclonal antibody, from tumour-draining lymph nodes. A series of novel assay systems, initially developed and characterised using melanoma reactive mouse monoclonal antibodies, were sequentially employed for the selection of human antibody exhibiting high tumour specificity. Several clones producing melanoma reactive human antibody were established. Clone MDT. 1 was selected for further characterisation, because of its highly selective reactivity against viable melanoma and other neuroectodermal cell lines, but lack of reactivity against other common malignant and non-malignant cell lines. Such restricted cell reactivity is characteristic of reactivity with class 2 tumour associated antigens. MDT. 1 was shown, in ELISA, to exhibit reactivity to ganglioside antigens GD3, GD2, GD1b, GM3 and GM2. These antigens are commonly associatedw ith the malignant transformation of melanocytes and other neuroectodermal cells. Enzymatic modification of GM3, with neuraminidase, identified the reactive minimal essential epitope as Neua2- 3Galß1-4GIc-. Reactivity with rat monoclonal antibody 9G4 and molecular analysis showed MDT. 1 is encoded by the highly conserved VH4 gene, VH4-21. Like other VH4-21 encoded autoantibodies MDT. 1 exhibits reactivity with the cold agglutinin T. Analysis of the structures of `i' and sialogangliosides has identified similar structural epitopes, which may confer MDT. 1 reactivity. VH4-21 encoded autoantibody 216 exhibits similar reactivity with tumour associated ganglioside antigens as MDT. 1. Sialo-ganglioside/`i' reactive VH4-21 encoded antibodies, could therefore represent an important aspect of autoantibodies in the overall host immune response to tumour.

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Sodre, De Castro Laino Andressa. "Targeting Histone Deacetylases in Melanoma and T-cells to Improve Cancer Immunotherapy." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6144.

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Histone deacetylases (HDACs) are key mediators of gene expression and, thus, major regulators of cell function. As such, HDACs play a role in orchestrating tumor biology, and the use of small inhibitors targeting theses proteins is attractive for the field of cancer therapy. Indeed, several HDAC inhibitors have received FDA-approval for the treatment of malignancies, while a myriad of these compounds continue to be evaluated in clinical trials. Besides their direct impact on tumor growth, HDAC inhibitors have been shown to increase immunogenicity of cancer cells, facilitating generation of a productive immune response against tumors. Immunotherapeutic approaches take advantage of the intrinsic ability of the immune system to manifest an anti-tumor response. Mechanisms of immune escape are often developed by cancer cells, neutralizing activity of the immune system. For example, upregulation of the PD1 ligands PDL1 and PDL2 by tumor cells negatively regulates the anti-tumor functions of PD1-expressing infiltrating T-cells. Importantly, strategies targeting this inhibitory axis have shown outstanding clinical benefit for the treatment of solid and hematological malignancies. The mechanisms by which HDAC inhibitors modulate tumor and immune cells biology were explored herein. Initially, treatment of melanoma cells with pan- and class I-selective HDAC inhibitors resulted in upregulation of PDL1 and PDL2 molecules. These effects were observed in mouse and human cell lines, as well as in tumor cells resected from metastatic melanoma patients. This upregulation was robust and sustained, lasting at least 96 hours in vitro, and validated in vivo using a B16F10 syngeneic mouse model. Enhanced expression of PDL1 mediated by HDAC inhibitors was found to result from enhanced histone acetylation at the PDL1 gene promoter region. Combination therapy of HDAC inhibition and PD1 blockade was explored in the tumor setting, leading to synergistic effects in terms of reducing melanoma progression and increasing survival of B16F10 melanoma-bearing mice. These data provide a clinical rationale for combination therapy of epigenetic modifiers (e.g. HDAC inhibitors) and PD1 blockade as means to augment cancer immunotherapy, improving patient outcomes. As a second pillar of this research, the impacts of HDAC-selective inhibition were explored on immune cell biology, since the broad nature of pan-HDAC inhibitors was shown to be detrimental to T-cells in vitro and in vivo. Based on screening assay results, novel implications of treating melanoma patient T-cells ex vivo with the HDAC6-selective inhibitor ACY1215 were investigated. Treatment with this compound was unique among pan- and isotype-selective HDAC inhibitors in modulating T-cell cytokine production and showing minimal impact of T-cell viability. ACY1215 tempered Th2 cytokine production (i.e. IL-4, IL-6 and IL-10), and maintained Th1 effector cytokines (e.g. IFNγ and IL-2). Furthermore, ACY1215 increased expression of surface markers, including CD69 activation marker and ICOS co-stimulatory molecule. In addition, ACY1215 treatment enhanced accumulation of central memory T-cells during ex vivo expansion of tumor infiltrating T-cells harvested from resected tumors of metastatic melanoma patients. Importantly, ACY1215-mediated inhibition improved tumor-killing capacity of T-cells. These results highlight an unexplored ability of selective HDAC inhibitor ACY1215 to augment T-cell expansion during protocols of adoptive cell therapy. While the discoveries presented here warrant further investigation of cellular and molecular mechanisms associated with ACY1215-treated T-cells, the clinic implications are clear and rapidly translatable.

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Shridhar, Naveen [Verfasser]. "Novel vaccination strategies for CD4+ T cell immunotherapy of melanoma / Naveen Shridhar." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/119893378X/34.

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Karagiannis, Panagiotis. "Dissecting humoral immune responses in melanoma and the design of antibody immunotherapy." Thesis, King's College London (University of London), 2014. https://kclpure.kcl.ac.uk/portal/en/theses/dissecting-humoral-immune-responses-in-melanoma-and-the-design-of-antibody-immunotherapy(1b263e41-dedd-4d98-a045-97bfd6fa6f0b).html.

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Antibodies against melanoma antigens have been detected in patients but, despite known regulatory and activatory functions attributed to humoral immunity, the roles of B cells in solid tumours such as melanoma are inadequately understood. Insights into humoral responses and mechanisms of tumour-induced immune escape may in-form the design of more effective antibodies. The aims of this thesis are three-fold: a) to gain insights into regulatory mechanisms in tumour microenvironments that influence antibody expression; b) to examine whether humoral immune responses are associated with clinical outcomes with a view of defining biomarkers for melanoma; and c) to design antibody therapeutic strategies that may be less prone to tumour-induced immunomodulatory mechanisms. Th2-biased microenvironments favour production of IgG4 subclass antibodies, mainly through local expression of IL-10. Since IL-10 is expressed locally in melanoma tu-mours, B cell infiltration, IgG expression, cytokine production and IgG subclass distribution in melanoma tissues (n=57) were investigated and compared to samples from health volunteers (n=26). Consistent with Th2-biased inflammation, CD22+ and IgG4+ B cells infiltrated melanoma lesions. When cultured together ex vivo, B cells secreted increased VEGF and IgG4, while tumour cells enhanced IL-10 secre-tion. Two antibodies (IgG1, IgG4) against the tumour-associated antigen CSPG4 were engineered to examine the functional significance of IgG4 subclass. Despite ac-cumulation in tumours, anti-CSPG4 IgG4, in contrast to anti-CSPG4 IgG1, did not trigger effector cells to kill tumours in vitro and in vivo. IgG4 mediated IgG1 block-ade through the reduction of FcγRI activatory signalling, reducing immune effector cell capacity, and significantly impairing the potency of IgG1 in a humanised mouse model of cutaneous melanoma. Since IgG4 may impair anti-tumoural immunity, correlations between IgG4 serum levels and clinical outcomes were studied. Increased IgG4/IgGtotal ratios (G4-levels) in melanoma patient sera (n=173) were seen compared to those of healthy volun-teers (n=104). G4-levels were predictive of disease progression (ROC Curve analysis z=0.62; p=0.0065). Using 0.034 as a cut-off for G4-levels (Youden Index) higher ex-pression correlated with decreased progression-free survival (median 694 days; hazard ratio 2.559; 95% CI 1.555 to 4.211; p=0.0004) and overall survival (median 879 days; hazard ratio 1.871; 95% CI 1.0.45 to 3.349; P=0.035). These findings suggest that IgG4 may be further evaluated as a putative biomarker in sera of patients with melanoma. Tumour immune evasion may be overcome by employing antibodies less prone to Fcγ-mediated blockade, such as those of the IgE class. Two antibodies, anti-CSPG4 IgG1 and anti-CSPG4 IgE induced significant tumor cell death by differential mecha-nisms: antibody-dependent cell-mediated phagocytosis and antibody-dependent cell-mediated cytotoxicity, respectively, by human monocytes in vitro. Anti-CSPG4 IgE was however superior to IgG1 (p < 0.05) in restricting subcutaneous human melanoma tumour growth in a humanized mouse model. IgE efficacy was confirmed in an or-thotropic patient tumour in mice populated with autologous patient PBMCs. In summary, this thesis reports a novel pathway of tumour evasion through melanoma favouring production of IgG4 subclass antibodies; provides evidence that IgG4 can be considered as a putative biomarker in melanoma and demonstrates a possible strategy to overcome Fcγ-mediated blockade by designing an IgE antibody against a melanoma-associated antigen and demonstrating its superiority to IgG1.

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Riding, Rebecca L. "The Role of Type I Interferon in Vitiligo Pathogenesis and Melanoma Immunotherapy." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1065.

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Vitiligo is an autoimmune skin disease in which the pigment producing cells of the epidermis, melanocytes, are targeted for destruction by CD8+ T cells specific for melanocyte/melanoma-shared antigens. Previous work has identified IFNg as the central cytokine driving disease pathogenesis in both human patients and in our mouse model of vitiligo. IFNg signaling induces production of the chemokines CXCL9 and CXCL10, which trigger autoreactive T cell migration into the epidermis where effector T cells can target and destroy melanocytes. However, both IFNg and type I IFN signaling through activation of STAT1 proteins can induce transcription of the chemokines CXCL9 and CXCL10. Therefore, it seems reasonable that type I IFN signaling may also contribute to disease pathogenesis. The role of type I IFN in vitiligo is still unclear. Genome wide association studies identified multiple genes within the type I IFN pathway including TICAM1 and IFIH1 as susceptibility loci in vitiligo. One additional study reported increased epidermal staining of CD123, a marker expressed by pDCs, and the type I IFN induced gene MX1 in vitiligo patient skin. However, this study did not show any functional data to support the role of type I IFN signaling in vitiligo pathogenesis. Since the role of type I IFN in vitiligo is ill-defined, we used two different mouse models of vitiligo to functionally determine the role of type I IFN in disease by inducing vitiligo in hosts which lack the type I IFN receptor (IFNaR). In the first model, we induced vitiligo by adoptive transfer of melanocyte-specific CD8 T cells, which are activated in vivo by infection with recombinant vaccinia virus (VACV) expressing their cognate antigen. Vitiligo induction in IFNaR-deficient mice led to the development of severe disease compared to wild type mice. Acceleration and severity of disease was characterized by increased early recruitment of melanocyte-specific CD8 T cells to the skin, increased production of effector cytokines TNFa and IFNg, and reduced PD-1 expression. Increased production of IFNg by CD8 T cells in the skin of IFNaR-deficient mice led to increased expression of the chemokines CXCL9 and CXCL10 driving disease progression. IFNaR-deficient mice also displayed significantly increased VACV titters compared to wild type hosts. This data reveals a role of type I IFN in the clearance of recombinant VACV. This data also suggests that persistent VACV infection and prolonged antigen exposure in IFNaR deficient hosts is likely driving enhanced activation of melanocyte specific CD8 T cells and the subsequent development of severe vitiligo. Since melanocytes and melanoma cells express shared antigens that can be recognized by CD8 T cells, and because the development of vitiligo after melanoma immunotherapy is a positive prognostic factor for patients, we asked whether VACV vaccine therapy in IFNaR deficient mice would enhance the anti-tumor response to melanoma. B16-F10 inoculated wild type and IFNaR-deficient mice received adoptive transfer of melanocyte-specific CD8 T cells in combination with vaccinia virus expressing their cognate antigen to activate the cells in vivo. Treatment of adoptive T cell transfer and infection with VACV in IFNaR-deficient mice revealed significantly reduced tumor burden compared to wild type mice. Improved tumor regression in IFNaR-deficient hosts was characterized by increased infiltrating cytotoxic T lymphocytes and reduced PD-1 expression. These results further demonstrate that in the absence of type I IFN, hosts mount a robust cytotoxic CD8 T cell response against melanocyte/melanoma antigens and this is likely a result of persistent VACV that leads to prolonged CD8 T cell priming. As a result, IFNaR deficient hosts kill tumor cells more efficiently. To determine whether type I IFN regulates disease pathogenesis in the absence of virus infection, we generated a model of vitiligo in which bone marrow derived dendritic cells (BMDCs) pulsed with the cognate antigen were used to prime melanocyte-specific T cells in place of the viral vector. Induction of vitiligo in IFNaR-deficient hosts using BMDCs revealed no significant differences in disease score compared to wild type hosts. This data clearly demonstrates that type I IFN, in contrast to IFNg, is not required during the effector stage of vitiligo pathogenesis in mice. However, since we intentionally activate transferred melanocyte-specific CD8 T cells with VACV or BMDCs expressing their cognate antigen, our mouse models may circumvent the role of type I IFNs in initiating activation of autoreactive cells and driving autoimmunity. Type I IFN is critical for providing innate immune signals that drive the priming of autoreactive T cells through maturation of DCs by inducing antigen presentation, co-stimulatory molecule expression, and migration to the lymph nodes to encounter naïve T cells. Our mouse models of vitiligo may not capture this process. We have addressed this question by using a TLR ligand to activate BMDCs before transfer into hosts. In fact, activation of BMDCs before transfer leads to significantly enhanced vitiligo in mice and this is partially a result of type I IFN signaling on host cells. Thus, we provide evidence that type I IFNs can enhance the activation of melanocyte-specific CD8 T cells and drive autoimmunity. Collectively, our results show that type I IFN signaling has disparate effects on autoreactive T cell priming in a context dependent manner. We reveal that although type I IFN is not required for the effector phase of vitiligo in mice, maturation of DCs and subsequent type I IFN production can enhance the priming of autoreactive T cells and enhance vitiligo severity. Our studies also reveal that type I IFN is required to clear recombinant attenuated VACV infection and vaccine administration in IFNaR deficient hosts led to a robust autoreactive and anti-tumor response. These insights describing the role of type I IFN in autoimmunity and tumor immunology could have important implications for T cell dependent tumor immunotherapy.

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Engel, Christina [Verfasser]. "The influence of hypoxia on RIG-I-mediated melanoma immunotherapy / Christina Engel." Bonn : Universitäts- und Landesbibliothek Bonn, 2016. http://d-nb.info/1122193920/34.

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Guan, Xiangnan. "The Effects of Stromal and T cell Senescence on Melanoma." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1528720866526502.

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Brütting, Julia, Theresa Steeb, Lydia Reinhardt, Carola Berking, and Friedegund Meier. "Exploring the Most Visible German Websites on Melanoma Immunotherapy: A Web-Based Analysis." JMIR Publications, 2018. https://tud.qucosa.de/id/qucosa%3A33820.

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Background: Patients diagnosed with melanoma frequently search the internet for treatment information, including novel and complex immunotherapy. However, health literacy is limited among half of the German population, and no assessment of websites on melanoma treatment has been performed so far. Objective: The aim of this study was to identify and assess the most visible websites in German language on melanoma immunotherapy. Methods: In accordance with the common Web-based information-seeking behavior of patients with cancer, the first 20 hits on Google, Yahoo, and Bing were searched for combinations of German synonyms for “melanoma” and “immunotherapy” in July 2017. Websites that met our predefined eligibility criteria were considered for assessment. Three reviewers independently assessed their quality by using the established DISCERN tool and by checking the presence of quality certification. Usability and reliability were evaluated by the LIDA tool and understandability by the Patient Education Materials Assessment Tool (PEMAT). The Flesch Reading Ease Score (FRES) was calculated to estimate the readability. The ALEXA and SISTRIX tools were used to investigate the websites’ popularity and visibility. The interrater agreement was determined by calculating Cronbach alpha. Subgroup differences were identified by t test, U test, or one-way analysis of variance. Results: Of 480 hits, 45 single websites from 30 domains were assessed. Only 2 website domains displayed a German quality certification. The average assessment scores, mean (SD), were as follows: DISCERN, 48 (7.6); LIDA (usability), 40 (2.0); LIDA (reliability), 10 (1.6); PEMAT, 69% (16%); and FRES, 17 (14), indicating mediocre quality, good usability, and understandability but low reliability and an even very low readability of the included individual websites. SISTRIX scores ranged from 0 to 6872 and ALEXA scores ranged from 17 to 192,675, indicating heterogeneity of the visibility and popularity of German website domains providing information on melanoma immunotherapy. Conclusions: Optimization of the most accessible German websites on melanoma immunotherapy is desirable. Especially, simplification of the readability of information and further adaption to reliability criteria are required to support the education of patients with melanoma and laypersons, and to enhance transparency.

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Culp, W. David. "Identifying molecular targets for cancer therapy /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-188-3/.

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Sasse, André Deeke. "Quimioimunoterapia em melanoma maligno disseminado : revisão sistematica da literatura com meta-analise." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311536.

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Orientador: Otavio Augusto Camara Clark
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-06T13:39:36Z (GMT). No. of bitstreams: 1 Sasse_AndreDeeke_D.pdf: 24031684 bytes, checksum: 2accebd159f3ca01d70c9229968723b0 (MD5) Previous issue date: 2006
Resumo: RAZÕES: O melanoma maligno é o mais agressivo de todos os cânceres de pele, e sua incidência vem continuamente aumentando no mundo. O principal tratamento é a excisão cirúrgica da lesão primária, com intenção curativa em estágios iniciais. Os pacientes que apresentam doença metastática são considerados incuráveis, pois o melanoma é considerado refratário à maioria das terapias sistêmicas. Existem vários estudos prospectivos randomizados comparando diferentes esquemas de tratamento. Alguns estudos sugerem maior eficácia antitumoral combinando quimioterapia com imunoterapia, mas não existem evidências definitivas, pois comparações paralelas randoinizadas com tratamento com apenas quimioterapia apresentam resultados controversos. A conduta médica atual é baseada na opinião de especialistas, que determina qual é o tratamento considerado padrão. Frente a resultados controversos derivados de estudos randomizados, uma revisão sistemática da literatura faz-se necessária para determinar qual das abordagens terapêuticas apresenta ganhos reais para o paciente OBJETIVOS: Comparar os efeitos da quimioterapia associada à imunoterapia (quimioimunoterapia) com os da quimioterapia isolada em pacientes com melanoma maligno metastático. MÉTODOS: Revisão sistemática da literatura com meta-análise. Estudos clínicos randomizados no tratamento do melanoma metastático foram identificados, através de busca nas bases de dados Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, e LILACS. Referências de artigos encontrados, resumos de apresentações em congressos e bases de dados de estudos em andamento também foram utilizados para localizar estudos pertinentes. Critérios de inclusão: estudos controlados randomizados que compararam o uso de quimioterapia com o de quimioimunoterapia no tratamento de pacientes com qualquer idade, portadores de melanoma metastático. Dois revisores extraíram independentemente os dados dos artigos utilizando formulários de extração de dados. Quando possível, para cada desfecho clínico foi feita meta-análise com os dados extraídos, com o fim de calcular o efeito dos tratamentos entre os estudos. Os resultados da meta-análise são expressos com Risco Relativo (RR), Diferença entre os Riscos (DR) e Hazard Ratio (HR), com o correspondente intervalo de confiança (1C) de 95% Os desfechos clínicos avaliados foram sobrevida global, sobrevida em 1, 2 e 5 anos, taxas de resposta, sobrevida livre de progressão, toxicidade e qualidade de vida. RESULTADOS: No total, aproximadamente 1050 citações foram analisadas. 26 estudos foram inicialmente identificados Destes, 18 foram incluídos. A meta-análise dos dados mostra evidência de aumento das taxas de resposta objetiva [RR=1,40, IC95% 1,20 a 1,63; p<0,0001] em pacientes tratados com quimioimunoterapia, em relação aos tratados com quimioterapia. No entanto, o impacto deste aumento nas taxas de resposta não se traduziu em benefício em sobrevida [HR=0,89; IC95% 0,72 a 1,11; p=0,31]. Adicionalmente, há maior toxicidade hematológica e não-hematológica nos pacientes tratados com quimioimunoterapia, o que demonstra danos em relação ao benefício de aumento nas taxas de resposta. CONCLUSÃO: Há evidências de que de que a utilização de quimioimunoterapia não aumenta a sobrevida em pacientes com melanoma metastático. O aumento nas taxas de resposta não justifica a combinação de quimioterapia e imunoterapia fora do ambiente de estudos clínicos
Abstract: BACKGROUND: Malignant melanoma, the most aggressive of all skin cancers, is in increasing incidence throughout the world. Surgery remains the cornerstone of curative treatment in earlier stages. Metastatic disease is incurable in most patients, as melanoma is reputed as refractory to most systemic treatments. The combination of chemotherapy with immunotherapy has been reported to improve treatment results, but it is still unclear whether evidence exists to support this choice, compared with chemotherapy alone OBJECTIVES: To review and to compare the effects of therapy with chemotherapy plus immunotherapy (chemoimmunotherapy) versus chemotherapy alone in patients with metastatic malignant melanoma. METHODS: Systematic review, with meta-analysis. andomized controlled trials in the treatment of metastatic melanoma were identified. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and LILACS. References, conference proceedings, and databases of ongoing trials were also used to locate trials. We included all randomized controlled trials that compared the use of chemotherapy versus chemoimmunotherapy in the treatment of people with any age, diagnosed with metastatic melanoma. Two reviewers independently extracted the data from the articles using data extraction forms. Whenever possible, a meta-analysis was performed with the data extracted, in order to calculate a weighted treatment effect across trials For binary endpoints the risk ratio (RR) or the risk difference (RD) was calculated, and for time-to-event data, we calculated Hazard Ratio (HR), both with 95% confidence intervals. The endpoints evaluated were overall survival, one-, two-, and five- year survival rates, response rates, progression-free survival, treatment-related toxicity and quality of life measures. RESULTS: Approximately 1050 citations were scanned. We initially identified 26 studies. Of these, 18 studies were included This systematic review showed evidence of an increase of objective response rates [RR=1.40; 95%CI 1.20 to 1.63; p0.0001] in patients treated with chemoimmunotherapy, in comparison with patients treated with chemotherapy Nevertheless, the impact of these increased response rates in patients was not translated in a survival benefit [HR=0 89; 95%CI 0.72 to 1.11; p=0.31]. Additionally, we found increased hematological and non-hematological toxicities in patients treated with chemoimmunotherapy, which bring harms to the subjective vantage of increased responses. CONCLUSION: There is evidence that the use of chemoimmunotherapy does not increase survival in patients with metastatic melanoma. The improve in response rates did not justify the use of combination of immunotherapy and chemotherapy in chemoimmunotherapy regimens outside of clinical trials
Doutorado
Clinica Medica
Doutor em Clínica Médica

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Khazen, Roxana. "Dissecting early mechanism of melanoma cell resistance to cytotoxic T lymphocyte attack." Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30007/document.

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Les cellules de mélanome humain expriment différents antigènes tumoraux qui sont reconnus par les lymphocytes T cytotoxiques CD8 + (CTL) induisant des réponses spécifiques de la tumeur in vivo. Cependant, chez les patients atteints de mélanome l'efficacité de la réponse naturelle des CTL ou stimulée par thérapie est limitée. Les mécanismes sous-jacents de l'échec de la phase effectrice des CTL contre les mélanomes sont encore largement méconnus. Notre hypothèse est que l'efficacité limitée des CTL dans leur combat contre les tumeurs est le résultat d'une balance défavorable entre la capacité des CTL à tuer les tumeurs et une résistance tumorale intrinsèque à l'activité cytolytique des CTL. Au cours de ma thèse je me suis concentrée sur la dynamique moléculaire qui se produit à la synapse lytique afin de pouvoir identifier un mécanisme précoce mis en place par les cellules de mélanome face à l'attaque des CTL. En combinant l'utilisation d'approches de microscopie de pointe et des outils moléculaires, j'ai pu montrer que, lors de l'interaction avec les CTL, les cellules de mélanome humain subissent une activation de leur trafic vésiculaire endosomal et lysosomal, lequel est intensifié à la synapse lytique et corrèle avec la dégradation par la cathepsine de la perforine et un défaut de pénétration d'entrée du granzyme B. De plus, j'ai démontré que le blocage du trafic lysosomal dépendant de SNAP23, la modification du pH (intra-vésiculaire) et l'inhibition de l'activité lysosomale protéotlytique des cellules de mélanome permet de restaurer leur sensibilité à l'attaque des CTL. Nos résultats révèlent une stratégie sans précédent d' " auto-défense " des cellules de mélanome à la synapse immunologique basée sur une sécrétion lysosomale massive et sur la dégradation de la perforine sécrétée par les CTL. Ainsi pouvoir interférer avec cette stratégie synaptique d'auto-défense des cellules de mélanome pourrait contribuer à potentialiser les réponses des CTL et les immunothérapies chez les patients atteints de mélanome
Human melanoma cells express various tumor antigens that are recognized by CD8+ cytotoxic T lymphocytes (CTL) and elicit tumor-specific responses in vivo. However, natural and therapeutically enhanced CTL responses in melanoma patients are of limited efficacy. The mechanisms underlying the failure of CTL effector phase against melanomas are still largely elusive. Our hypothesis is that the limited efficacy of CTL in their fight against tumors is the result of an unfavorable balance between CTL ability to kill tumors and an intrinsic tumor resistance to CTL cytolytic activity. During my thesis I focused on the molecular dynamics occurring at the lytic synapse in order to identify possible "early response-mechanism" of melanoma cells to CTL attack. Using a combination of cutting edge microscopy approaches and molecular tools, I showed that upon conjugation with CTL, human melanoma cells undergo an exacerbated late endosome/lysosome trafficking, which is intensified at the lytic synapse and is paralleled by cathepsin-mediated perforin degradation and deficient granzyme B penetration. Abortion of SNAP-23-dependent lysosomal trafficking, pH perturbation or impairment of lysosomal proteolytic activity restores susceptibility to CTL attack. Our results reveal an unprecedented strategy of melanoma cell "self-defense" at the immunologic synapse based on a lysosome secretory burst and perforin degradation at the lytic synapse. Interfering with this synaptic self-defense strategy might be instrumental to potentiate CTL-mediated therapies in melanoma patients

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Mo, Xuan. "THE ROLE OF INTERFERON GAMMA AND CTLA4 IN MELANOCYTE AND MELANOMA BIOLOGY." Diss., Temple University Libraries, 2018. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/539103.

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Biomedical Sciences
Ph.D.
Ultraviolet radiation (UVR) stimulates melanogenesis in melanocytes, primarily via release of alpha-melanocyte stimulating hormone from keratinocytes. UVR also induced an inflammatory response in the skin in which Interferon-gamma (IFNγ) cytokine plays an important orchestrating role. Here we report that recombinant IFNγ induces a temporal increase of melanogenesis in mouse melanoma cells. IFNγ elevates expression of microphthalmia-associated transcription factor (Mitf), which is the master regulator of melanogenesis by initiating transcription of melanogenic enzymes, tyrosinase (Tyr), tyrosinese-related protein 1 (Tyrp1) and dopachrome tautomerase (Dct). Interestingly, tyrosinase protein, but not mRNA expression, accumulated in response to IFNγ treatment and was consistent with tyrosinase activity. In addition, glycosidase digestion showed that IFNγ induced ER-resistant, fully mature tyrosinase via post-transcriptional mechanisms, rather than increased de novo synthesis or early processing in the ER. Most strikingly, IFNγ mediated alkalization of melanosomes by elevating Oca2 expression, which leads to facilitate melanosome maturation and sequential accumulation of mature tyrosianse. Both Jak1/Jak2 inhibitor Ruxolitinib and knockout of Stat1 mediated by CRISPR-CAS9 blocked the IFNγ-induced Mitf, tyrosinase, Oca2 expressions and melanin biosynthesis. Our data reveals that IFNγ-Jak1/2-Stat1 axis regulates melanogenesis by inducing maturation of melanosomes and accumulation of mature tyrosinase via post-translational mechanisms. CTLA4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti-CTLA4 immunotherapy is highly effective at reactivating T cell responses against melanoma, which is postulated to be due to targeting CTLA4 on T cells. Here we report that CTLA4 is also highly expressed by most human melanoma cell lines, as well as in normal human melanocytes. Interferon-gamma (IFNγ) signaling activated the expression of the human CTLA4 gene in a melanocyte and melanoma cell-specific manner. Mechanistically, IFNγ activated CTLA4 expression through JAK1/2-dependent phosphorylation of STAT1, which bound a specific gamma-activated sequence (GAS) site on the CTLA4 promoter, thereby licensing CBP/p300-mediated histone acetylation and local chromatin opening. In melanoma cell lines, elevated baseline expression relied upon constitutive activation of the MAPK pathway. Notably, RNA-seq analyses of melanoma specimens obtained from patients who had received anti-CTLA4 immunotherapy (ipilimumab) showed upregulation of an IFNγ -response gene expression signature, including CTLA4 itself, which correlated significantly with durable response. We also show that ectopic expression of Ctla4 in mouse melanoma cells promotes tumor growth in immunocompetent mice. Ctla4-enhanced melanomagenesis is blocked in immunodeficient NSG mice. In addition, ligation of CD86 (one of Ctla4 ligands) in T cells inhibits CD8 T cells proliferation in vitro. Expression of Ctla4 in melanoma cells are resistant to CD8 T cell cytoxicity in vitro. Our data demonstrates and highlights the novel and unrecognized functions of CTLA4 in melanoma cells that aids their survival, immunoevasion and tumorigenic capabilities. Taken together, these findings have potential implications for the conventional and prototypical roles of the IFNγ signaling pathway and CTLA4 in tumor immunosurveillance and tumor immunoevasion. More importantly, our results raise the possibility that CTLA4 targeting on melanoma cells may contribute to the clinical immunobiology of anti-CTLA4 responses.
Temple University--Theses

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Messaoudene, Meriem. "Phenotypic and Functional Characteristics of Natural Killer (NK) Cells from Metastic Melanoma Patients." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T025.

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Les cellules Natural Killer (NK) sont de grands lymphocytes granuleux capables de rapidement éliminer des cellules tumorales et des cellules infectées par des virus sans immunisation au préalable. Au cours de ma thèse, j’ai analysé plusieurs paramètres impliqués dans la reconnaissance et la lyse des cellules de mélanome par les NK. J’ai montré à partir d’analyses ex vivo que les NK sanguines de patients atteints de mélanome métastatique (stade III-IV) présentent un faible potentiel lytique. Cependant, de telles NK provenant de patients mélanomes de tout stade clinique activées in vitro par de l’IL-2 lysent efficacement des lignées de mélanome métastatique. L’analyse du phénotype de NK circulantes de patients stade IV a montré une diminution de l’expression du récepteur activateur NKp46/NCR1 comparé aux NK de donneurs sains. J’ai également montré une corrélation positive entre l’expression du NKp46 à la surface des NK et la durée du stade IV. Pour caractériser les NK infiltrant le mélanome, J’ai analysé ex vivo les NK infiltrant des ganglions métastatiques (GG) provenant de 25 patients en stade III. Les GG de patients mélanomes contiennent une population unique de NK CD56brightCD16+ représentant 50% des NK dans ces GG qui expriment fortement les récepteurs NK NCR, NKG2D, KIRs et produisent une plus forte proportion de perforin comparée aux NK CD56brightCD16- ganglionnaires. Les NK immunsélectionnées à partir de GG et activées avec de l’IL-2 ou de l’IL-15 lysent rapidement et efficacement des lignées cellulaires de mélanome. Elles sont caractérisées par des capacités lytiques supérieures aux NK sanguines. De plus, afin d’évaluer l’impact des NK au cours du mélanome, j’ai analysé in situ les NK infiltrant des ganglions sentinelles positive et négatif ainsi que des tumeurs cutanées primaires. Les NK sont faibles dans les GS ; cependant nous avons montré que le nombre de NK infiltrant ces ganglions sentinelles est associé à une plus forte rechute à cinq ans des patients. Les cellules NK infiltrant les tumeurs cutanées sont présentes préférentiellement dans la zone peritumorale et sont très rares dans la tumeur.Chez les patients atteints de mélanome, les NK sanguines et infiltrant les tumeurs ont des caractéristiques phénotypiques et fonctionnelles différentes. Une meilleure compréhension de telles différences doit être prise en compte, ainsi la biologie des NK et de leur modulation au cours du cancer est nécessaire pour développer une stratégie thérapeutique à base de cellules NK efficace
Cytotoxic immune effectors can control the development and growth of certain solid tumours. Among these cytotoxic effectors, NK cells are capable of rapidly eliminating tumour cells and virus-infected cells without prior immunization.The objectives of my thesis were to evaluate the potential role of NK cells in the immune response against melanoma. First, I have characterized the functional status of blood NK cells from melanoma patients at different stages of the disease. I showed that ex vivo NK cells from most advanced stage III-IV patients display low lytic potential. However, IL-2-activated NK cells from patients efficiently lyse melanoma cells and that independently to the clinical stage. Moreover, the expression of the activating receptor NKp46/NCR1 by blood NK cells was decreased in stage IV patients compared to healthy donors, and a positive correlation between NKp46 expression by NK cells and the duration of stage IV was found. I have also characterized ex vivo NK cells infiltrating metastatic lymph nodes (M-LN) from stage III melanoma patients. I have identified in M-LN a unique subpopulation of mature CD56brightCD16+ NK cells that expressed higher NCR, NKG2D, KIRs, and perforin levels than CD56brightCD16- NK cells counterpart. NK cells from M-LN activated with IL-2 or IL-15, rapidly lysed metastatic melanoma cell lines with higher efficiency than autologous blood NK cells. Finally, to determine if NK cells display a prognostic value, I analysed by immunohistochemistry NK cells and other immune cells infiltrating positive and negative sentinel lymph nodes (SLN). SLN are characterized by high densities of macrophages and endothelial cells, even higher in SLN+. Few NK cells and Granzyme B+ cells infiltrate SLNs while CD8+ T cells are numerous. Moreover, numbers of NK cells in SLN correlated with higher rate of 5 year-relapse of patients. Compared to SLN, primary cutaneous melanomas contain high numbers of NK cells that are preferentially localized in the periphery of the tumour and are not related to the Breslow. My findings showed that in melanoma patients, circulating and tumour infiltrating NK cells display unique phenotypic and functional characteristics, indicating that tumour may alter their function. However, they respond to cytokine activation and acquire antitumor lytic potential. In the new landscape of melanoma treatment, NK cells are worthy to be considered for combined treatment with BRAF inhibitors

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Stemke, Anastasia [Verfasser], and Viktor [Akademischer Betreuer] Umansky. "Immunotherapy with tumor antigenspecific T cells in ret transgenic mouse melanoma model / Anastasia Stemke ; Betreuer: Viktor Umansky." Heidelberg : Universitätsbibliothek Heidelberg, 2013. http://d-nb.info/1177382385/34.

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Tsur, Neta [Verfasser], and Markus [Akademischer Betreuer] Morrison. "Predicting response to immunotherapy in metastatic melanoma by a personalized mathematical model / Neta Tsur ; Betreuer: Markus Morrison." Stuttgart : Universitätsbibliothek der Universität Stuttgart, 2020. http://d-nb.info/1215574142/34.

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Effern, Maike [Verfasser]. "Modelling melanoma control by immunotherapy and tissue-resident memory T cells using CRISPR/Cas9-based approaches / Maike Effern." Bonn : Universitäts- und Landesbibliothek Bonn, 2020. http://d-nb.info/1229989064/34.

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Schiza, Aglaia. "Experimental treatment of patients with disseminated malignant melanoma." Doctoral thesis, Uppsala universitet, Experimentell och klinisk onkologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-330710.

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Malignant melanoma (MM) is the deadliest skin cancer with an ever-increasing incidence. New treatments have improved the prognosis for patients with advanced MM. Still, most patients do not respond, and the side effects can be severe, underlining the need for better therapies. The overall aim of this thesis was to evaluate new means to improve the treatment for patients with advanced MM. Immunostimulatory gene therapy (AdCD40L) was evaluated in a clinical study and BRAF-inhibitory treatment in rare cases of BRAF-mutated MM. Due to its immunogenicity, MM is an attractive target for immunostimulatory gene therapy. AdCD40L is an adenovirus carrying the human gene for CD40 ligand, which in different ways can stimulate the immune system to combat cancer. We conducted a Phase I/IIa study with AdCD40L in patients with metastatic MM having received established treatments. In cohort 1 (n=6), four weekly, intratumoural AdCD40L injections were given. In cohort 2 (n=9), low dose cyclophosphamide was added to increase the immune response. Since irradiation may act synergistically with immunotherapy, patients in cohort 3 (n=9) also received a single fraction of radiotherapy (8 Gy). This fraction was given towards the lesion selected for injections. The primary objectives were to assess the feasibility and safety of AdCD40L-treatment and secondarily its anti-tumour effects. Patients were thoroughly assessed for toxicity. The anti-tumour response was evaluated by imaging techniques (FDG-PET/CT, DW-MRI scans), tumour biopsies and blood tests. Plasma protein markers were measured with a multiplex platform. Another objective was to evaluate the potential of DW-MRI and FDG-PET/CT for prediction of AdCD40L treatment response, in terms of overall survival (OS). AdCD40L was well tolerated with mild transient reactions. Local and distant responses in PET/CT scans along with a significantly better 6-month survival in the cohorts that received cyclophosphamide conditioning were observed. Effector lymphocyte responses were elicited. All patients had an increased T effector/T regulatory-cell ratio and death receptors were significantly up-regulated post therapy. Inflammatory cytokines and other plasma proteins were altered in favourable ways by the AdCD40L treatment. The analyses support that the functional DWI parameters may be better early predictors of OS than the established metabolic and morphologic criteria of FDG-PET/CT and CT/MRI, respectively. In conclusion, the stimulation of the CD40 pathway to initiate anti-tumour immunity is a promising treatment alternative for MM patients. However, further studies with developed treatment schemes are warranted. In the first report ever on treatment of a pregnant patient with a BRAF-inhibitor, the therapy was initiated in the second trimester. The treatment with vemurafenib enabled prolonged gestation, hence reducing the risk of immaturity-related complications. Further, we report the first case worldwide of a patient with metastatic conjunctival melanoma who benefitted from treatment with vemurafenib. Additional studies are needed to assess the efficacy of BRAF -inhibitors in the different subtypes of ocular melanoma.

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Zimmerer, Jason Michael. "Interferon-alpha immunotherapy of melanoma signal transduction, gene transcription, and the role of suppressor of cytokine signaling proteins in immune cells /." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1173305217.

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Simon, Bianca [Verfasser], Falk [Akademischer Betreuer] Nimmerjahn, and Falk [Gutachter] Nimmerjahn. "Optimization of engineered T cells for the use in melanoma immunotherapy / Bianca Simon ; Gutachter: Falk Nimmerjahn ; Betreuer: Falk Nimmerjahn." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2020. http://d-nb.info/1204257809/34.

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Cywinski, Adele Lynsey. "The generation and in vitro characterisation of EBV B-LCL x melanoma hybrid cells as potential candidates in tumour immunotherapy." Thesis, University of Leicester, 2000. http://hdl.handle.net/2381/29808.

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In this study, human derived melanoma cell lines (518.A2, Gerl43 and DAUV) were fused with EBV B-LCL (HMy2) using polyethylene glycol as the fusogen. Although the hybrid cells had a dominant tumour cell phenotype and did not express the co-stimulatory ligand molecules CD80 or CD86, they showed a significant increase in their ability to stimulate primary allogeneic T cell responses in vitro, as compared with the parent melanoma cells. The MHC class I(+), MHC class II(-) hybrid cells (518.A2 x HMy2) were able to directly stimulate separated CD8+ T cells, but not CD4+ T cells, whereas the MHC class I(+), MHC class II(+) hybrid cells (HMy2 x Gerl43) were able to directly stimulate both CD4+ and CD8+ T cell subsets. The T cell response was independent of CD80/CD86 interaction with CD28/CTLA-4, as the response could not be blocked with CTLA-4 Ig. Bystander non-T cell co-operation enhanced the T cell responses to the hybrid cells, by providing CD80/CD86 dependent co-stimulatory signals. Genetic modification of Gerl43 and the HMy2 x Gerl43 hybrid cells to express CD80 significantly increased the level of direct CD3+ T cell proliferation, compared with the non-transfected cells. The HMy2 x 518.A2 and HMy2 x Gerl43 hybrid cells retained expression of tumour-associated antigens, as determined by RT-PCR, and were antigenically stable in vitro. HMy2 x 518.A2 clone 2 expressed tumour-associated antigens at greater levels than the parent melanoma cells, and was able to present MAGE 1 and MAGE 3 antigens to HLA class I-restricted, antigen specific CTL clones with grater efficiency than the parent melanoma cell line. In addition, HMy2 x 518.A2 clone 2 was recognised by two anti-tyrosinase specific CTL clones, despite the expression of this antigen not being detected by RT-PCR. Overall, the data presented in this study supports the idea that APC x tumour cell hybrids have potential as candidates in tumour immunotherapy.

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Crosby, Brendan. "Exercise as an adjunct therapy in melanoma patients undergoing checkpoint inhibitor therapy." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2022. https://ro.ecu.edu.au/theses/2569.

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Extensive research has shown that exercise can improve physical, functional, and psychosocial outcomes during cancer treatment. Despite the prevalence of melanoma, exercise as a therapy in the management of this disease remains understudied and underrepresented in current exercise oncology guidelines. Our systematic literature review identified six studies (882 patients) reporting the effects of physical activity and exercise on objectively-measured and patient-reported outcomes among patients with melanoma. Studies presented heterogeneity of design with two cross-sectional surveys, two retrospective analyses, and two non-randomised intervention trials. Findings from this review indicate that physical activity or exercise did not negatively impact quality of life, objectively measured or patient-reported outcomes in patients with melanoma. In our intervention study, ten patients (5 female, 62.2 ± 13.6 years) with advanced melanoma receiving checkpoint inhibitors completed the 8-week single-group telehealth intervention. Intervention sessions were undertaken three times per week (24 sessions) and included supervised comprehensive balance, aerobic, and resistance exercises. The completion rate was 91%, program attendance 88%, average session intensity 76%, with no severe or life-threatening adverse events. Physical function outcomes, aerobic capacity (17.6%, p < 0.001), lower body power (23.2%, p = 0.006), upper body strength (39.6%, p = 0.010), and balance (3.8%, p = 0.007) improved following the intervention. There was no change in quality of life (p = 0.888) or fatigue (p = 0.440), although the decrease in fatigue [(median and IQR, 44.4 (22.2 – 66.7) to 33.3 (19.4 – 47.2)] was clinically meaningful. These findings show that supervised exercise delivered via telehealth to patients with advanced melanoma receiving checkpoint inhibitors is feasible and can improve physical function. Supervised telehealth exercise is safe and can be delivered by an accredited exercise physiologist to improve physical outcomes and preserve quality of life in patients undergoing checkpoint inhibitor treatment.

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Mendes, Priscila Fraga Penteado [UNIFESP]. "Identificação, por anticorpo monoclonal, de proteína de 230 kDa relacionada com malignidade em melanoma murino." Universidade Federal de São Paulo (UNIFESP), 2006. http://repositorio.unifesp.br/handle/11600/9703.

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Made available in DSpace on 2015-07-22T20:50:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-12-31
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Melanomas se destacam entre os tumores sólidos por apresentar alto potencial de malignidade e incidência crescente, especialmente entre indivíduos jovens. Identificação de marcadores moleculares em melanomas é de enorme interesse para uso clínico e para estudos relacionados ao seu desenvolvimento. A linhagem de melanoma murino B16 tem sido amplamente empregada visando melhor compreensão do processo metastático. Objetivo: identificar moléculas na superfície de células B16, empregando anticorpos monoclonais, que apresentem função biológica importante para essas células, bem como investigar expressão de moléculas reconhecidas pelos mesmos mAbs em melanoma humano. Métodos: camundongos C57Bl/6 foram imunizados com células B16 irradiadas para produção de híbridos produtores de mAb. Resultados: após fusão foi obtido mAb da classe IgM, designado G12F2, que reconheceu uma única banda de aproximadamente 230 kDa em extrato total de células B16. A molécula era expressa na superfície celular e não por células não tumorigênicas, como fibroblastos ou melanócitos melan-a. Células não tumorigênicas, derivadas de melan-a, também não a expressaram ao passo que células tumorigênicas, de mesma origem, expressaram-na em grande quantidade. Variante menos metastática da linhagem B16 expressou menor quantidade desta molécula quando comparado à variante mais metastática. A neutralização da molécula de 230 kDa com mAb G12F2 inibiu proliferação, migração e invasão por células B16 in vitro. Também nestas condições, G12F2 promoveu atividade citolítica contra células B16, mediada por complemento. Por outro lado, adição in vitro de mAb G12F2 em nada alterou adesão das células B16 à fibronectina e laminina, ou adesão célula-célula. In vivo, o tratamento com mAb G12F2 inibiu crescimento do nódulo tumoral e formação de metástases pulmonares. Quando testado contra extrato de tumores de origem humana, como carcinoma e melanoma, mAb G12F2 reconheceu banda de 75 e 67 kDa, respectivamente. Por fim, foi demonstrado que mAb inibiu proliferação de células de melanoma humano in vitro. Conclusões: a molécula de 230 KDa parece ter importância durante crescimento do melanoma murino; identificação de molécula homóloga em melanoma humano fornecerá subsídios para diagnóstico e protocolos visando imunoterapia.
TEDE
BV UNIFESP: Teses e dissertações

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Neto, Adalberto Alves Martins. "Desvio da resposta imunológica deflagrada por morte celular em melanoma experimental pelo imunoestimulador P-MAPA: uma potencial estratégia antitumoral dependente da ativação de receptores TOLL-LIKE?" Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-30012018-114417/.

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O melanoma é o mais agressivo tumor da pele, cuja resistência aos tratamentos quimioterápicos tem promovido a crescente utilização de imunoquimioterapia, como é o caso da utilização de agonistas dos receptores Toll-Like (TLRs). Nesse contexto, os compostos abreviados por P-MAPA e seu sintético estrutural MRB-CFI-1 com reconhecidas propriedades antitumorais e imunológicas, são fortes candidatos na terapia e prevenção desse tipo de câncer. Esse estudo visa determinar o potencial anticâncer do P-MAPA e de MRB-CFI-1 contra o melanoma murino em consequência ao padrão de resposta microambiental semelhante ao de morte imunogênica, em regimes de tratamento terapêutico ou vacinal, na vigência de quimioterapia com cisplatina e/ou em associação com antígenos de células tumorais totais. Após avaliação In vivo do crescimento de tumores B16F10 implantados em modelos murinos selvagem e nocaute para o gene Myd88, na vigência ou não do tratamento com cisplatina e/ou P-MAPA, nossos resultados mostraram que o P-MAPA apresentou atividade pró-tumoral e antagonizou a ação da cisplatina em inibir o crescimento dos tumores, de forma dependente de Myd88. Além disso, através de análises qualitativa e quantitativa pelo software ImageJ em fotomicrografias de secções tumorais coradas histologicamente, observamos que o P-MAPA promoveu mudanças microambientais nos tumores que podem impactar negativamente em seu desempenho. Como monoterapia em esquema de vacinação com lisado tumoral total em combinação com quimioterapia, o P-MAPA em dose baixa falhou em suprimir o crescimento de tumores B16F10, mas o seu sintético MRB-CFI-1 foi capaz de prevenir o crescimento desse tipo de melanoma num regime de vacinação profilática. Apesar do sucesso terapêutico desse imunomodulador em diversos modelos de câncer e de doenças infecciosas, o P-MAPA não foi eficaz em produz respostas microambientais contra o melanoma murino, dados esses que limitam a aplicabilidade clínica do composto. De outro modo, o composto fosfato inorgânico MRB-CFI-1 foi protetivo em retardar o aparecimento desse tipo de doença. Assim, o presente estudo foi importante por ampliar o entendimento funcional do P-MAPA numa abordagem imunoquimioterápica em modelos biológicos de tumores de melanoma, e representa uma importante mudança na utilização de constituintes individuais similares ao P-MAPA que sejam mais eficazes, de fácil obtenção, e de produção controlada e garantida
Melanoma is the most aggressive skin cancer, whose resistance to chemotherapeutic treatments has promoted the increasing use of immunochemotherapy, as is the case for the use of Toll-Like receptor agonists (TLRs). In this context, the compounds abbreviated by P-MAPA and its structural synthetic MRB-CFI-1 with recognized antitumor and immunological properties are strong candidates in the therapy and prevention of this type of cancer. This study aims to determine the anti-cancer potential of P-MAPA and MRB-CFI-1 against murine melanoma as a consequence of the microenvironmental response pattern similar to that of immunogenic death in therapeutic or vaccine treatment regimens when using chemotherapy with cisplatin alone or in combination with whole tumor cell antigens. After In vivo evaluation of the growth of B16F10 tumors implanted in wild-type and Myd88 gene knockout mice, under treatment or not with cisplatin and / or P-MAPA, our results showed that P-MAPA showed pro-tumor activity and antagonized the action of cisplatin in inhibiting the growth of tumors in a Myd88-dependent manner. In addition, using qualitative and quantitative analysis by ImageJ software in histological images of tumor sections, we observed that P-MAPA promoted microenvironmental changes in tumors that may negatively impact its performance. As monotherapy in vaccination schedule with total tumor lysate in combination with chemotherapy, low dose P-MAPA failed to suppress the growth of B16F10 tumors, but its synthetic MRB-CFI-1 was able to prevent the growth of this type of melanoma in prophylactic vaccination regimen. Despite the therapeutic success of this immunomodulator in various cancer models and infectious diseases, P-MAPA has not been effective in producing microenvironmental responses against murine melanoma, data that limit the clinical applicability of the compound. Otherwise, the inorganic phosphate compound MRB-CFI-1 was protective in delaying the onset of this type of disease. Thus, the present study was important because it broadened the functional understanding of P-MAPA in an immuno-chemotherapeutic approach in biological models of melanoma tumors and represents an important change in the use of individual constituents similar to P-MAPA that are more efficient, easily obtainable, and controlled and guaranteed production

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Arakelian, Tsolère. "Impact of Targeting the Autophagy Related Gene Beclin 1 on the Immune Landscape of Melanoma." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS193.

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L'immunothérapie basée sur le blocage des points de contrôle immunitaire (ICBs) est un traitement prometteur pour les patients atteints de mélanome ; cependant, seule une petite sous-population en tire un bénéfice à long terme. Un des défis pour améliorer l'efficacité et étendre le bénéfice des ICBs aux patients non répondeurs est de concevoir des approches innovantes permettant de transformer les tumeurs dites "froides ou désertes pour les cellules immunitaire" en tumeurs dites "chaudes ou infiltrées par les cellules immunitaires" qui sont éligibles aux ICBs. Nous avons étudié l'impact du ciblage du gène de l'autophagie Beclin1 sur le paysage immunitaire des tumeurs de mélanome B16-F10. Nos résultats ont démonté que ce ciblage inhibait significativement la croissance tumorale B16-F10 et augmentait l'infiltration des leucocytes CD45+. Le phénotypage immunitaire a révélé une augmentation de l'infiltration de cellules NK (Natural Killer) actives, de macrophages inflammatoires et résidents de type 1, de cellules dendritiques et de lymphocytes T CD8+ actifs. L’inhibition de la croissance tumorale Becn1- n'était plus observée par la déplétion des CD8+ de l'hôte, soulignant ainsi leur rôle dans le contrôle du développement de ces tumeurs. Nos résultats ont démontré que La régulation du paysage immunitaire des tumeurs Becn1- était associée à une modulation du réseau de cytokines/chémokines dans le microenvironnement tumoral (TME). Ainsi, les tumeurs Becn1- présentaient une signature de cytokines inflammatoires (comprenant CCL5, CXCL10 et IFNg) qui pourrait être responsable de l'établissement de microenvironnement inflammatoire permissif aux cellules CD8. Nous avons révélé que la surexpression de l'IFNg dans le TME des tumeurs Becn1- était responsable de l'induction de PD-L1 sur les cellules tumorales par la voie d'activation JAK/STATs. En conclusion, cette étude met en évidence Beclin1 comme une cible majeure, capable d'induire l'infiltration des cellules effectrices immunitaires dans les mélanomes en induisant une signature inflammatoire. Elle fournit également la preuve de concept pour combiner des inhibiteurs d'autophagie avec les ICBs comme une approche de pointe pour améliorer leur efficacité
Immune Checkpoint Blockades (ICBs)-based immunotherapy has emerged as a promising treatment for melanoma patients; however only a small subset of patients reaps a long term benefit. One of the major challenges to enhance the efficacy and extend the benefit of ICBs to non-responder patients is to design innovative approaches allowing the switch of “immune desert cold tumors” to “immune infiltrated hot tumors" which are eligible for ICB-based therapies. Here, we investigated the impact of targeting the early autophagy gene Beclin1 on the immune landscape of B16-F10 melanoma tumors. We found that targeting Beclin1 (Becn1-) significantly inhibited B16-F10 tumor growth and increased the infiltration of CD45+ leukocytes into the tumor bed. Immune phenotyping revealed an increased infiltration of active Natural Killer (NK) cells, inflammatory and resident type 1 macrophages, dendritic cells, and active CD8+ T lymphocytes. The inhibition of Becn1- tumor growth was no longer observed by depleting host CD8+ T cells, thus highlighting their major role in the control of Becn1- B16-F10 tumor development. We showed that Beclin1-dependent regulation of the immune landscape was associated with profound modulation of the cytokine/chemokine network in the tumor microenvironment (TME). Importantly, we revealed that Becn1- tumors displayed an inflammatory cytokine signature (comprised, but not restricted to, CCL5, CXCL10 and IFNg) that could be responsible for the switch from cold non T-inflamed to hot T-inflamed tumors. Mechanistically, we reported that the overexpression of IFNg in Becn1- TME was responsible for the induction of Programed Death ligand-1 (PD-L1) on tumor cells through the activation of JAK/STATs pathway. Overall, this study highlights Beclin1 as a valuable target, able to drive immune effectors cells into the melanoma tumors by inducing an inflammatory signature. This study provides the proof of concept for combining drugs inhibiting early autophagy process along with ICBs as a cutting-edge approach to improve their efficacy

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Giavina-Bianchi, Mara Huffenbaecher. "Análise da expressão da proteína NY-ESO-1 no melanoma cutâneo." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5133/tde-20062016-111434/.

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INTRODUÇÃO: o câncer é a doença que mais mata pessoas com idade abaixo de 85 anos e é um problema de saúde pública. Os tumores podem expressar em determinada fase de seu desenvolvimento proteínas anômalas que podem ser alvo de métodos diagnósticos e de intervenções terapêuticas. A expressão de NY-ESO-1 é detectada em 20 a 40% dos melanomas. Há evidências que esta expressão é mais freqüente em tumores de estágios mais avançados e está associada a um pior prognóstico. OBJETIVOS: determinar a frequência de expressão da proteína NY-ESO-1 no melanoma cutâneo e tentar correlacioná-la com o índice de Breslow, aspectos histopatológicos do melanoma, incluindo o infiltrado linfocítico tumoral, e a morbi-mortalidade dos pacientes. MÉTODOS: o presente estudo é longitudinal de coorte retrospectiva e foi realizado de agosto de 2009 a outubro de 2015. Foram selecionados 89 melanomas de 87 pacientes do Ambulatório de Tumores do Departamento de Dermatologia da FMUSP, divididos em 3 grupos, sendo: grupo 1: 34 melanomas com índice de Breslow <= 1,0 mm; grupo 2: 29 melanomas com índice de Breslow entre 1,1 - 4,0 mm e grupo 3: 26 melanomas com índice de Breslow >= 4,0 mm. As lâminas dos exames anátomo-patológicos destes pacientes foram revisadas quanto ao diagnóstico de melanoma, seu índice de Breslow e a presença de infiltrado linfocítico tumoral. A seguir, realizou-se exame de imunohistoquímica para a determinação da presença do antígeno NY-ESO-1 em todos os 89 tumores coletados e em mais 20 nevos (11 displásicos e 9 intradérmicos) escolhidos ao acaso. Através da revisão dos dados do prontuário, foram obtidos os dados clínicos de: idade, sexo, raça, fototipo da pele, local de aparecimento do melanoma, status do linfonodo sentinela quando realizado, desenvolvimento de metástases e sobrevida dos pacientes. Os dados anátomo-patológicos do tumor analisados foram: tipo histológico, presença de ulceração, e tipo de infiltrado linfocítico tumoral. Nos melanomas que apresentavam infiltrado linfocítico tumoral, foram realizados testes imunohistoquímicos para pesquisa de células CD3+, CD8+, FoxP3+ e CD8+FoxP3+ (duplamente positivas). RESULTADOS: O antígeno NY-ESO-1 esteve presente em 19% dos melanomas cutâneos primários e não foi detectado em nenhum dos 20 nevos pesquisados. A expressão do antígeno NY-ESO-1 esteve estatisticamente relacionada a tumores com espessuras maiores. Apresentou também uma associação inversa com o tipo extensivo superficial em relação aos outros tipos histológicos. O infiltrado linfocítico tumoral dos melanomas NY-ESO-1 positivos continha menor número de células CD3+, que se encontravam isoladas ou arranjadas em pequenos grupos de até 5 células, o que contrastava significantemente com os tumores NY-ESO-1 negativos, com maior densidade de células CD3+, dispostas em grandes grupos, com 6 ou mais células. A expressão da proteína NY-ESO-1 não esteve associada à idade, ao sexo, ao fototipo, ao sítio primário do tumor, à presença de ulceração, ao status do linfonodo sentinela, ao desenvolvimento de metástases ou à sobrevida. CONCLUSÕES: Há expressão de NY-ESO-1 em uma porcentagem considerável dos melanomas, principalmente nos mais espessos. O menor número de células CD3+ no infiltrado linfocítico tumoral, acrescido ao fato destas células estarem isoladas ou em pequenos grupos, sugere que embora imunogênico, a expressão do antígeno NY-ESO-1 não resulta num estímulo eficaz do sistema imune no combate ao tumor. O desenvolvimento de uma vacina para estes pacientes poderá, no futuro, aumentar as possibilidades terapêuticas do melanoma
INTRODUCTION: cancer is the disease that leads to the greatest number of deaths in people over 85 years old and it has become a major public health problem. Tumors may express aberrantly proteins during certain phases of their development, which can be target for diagnostic or treatment purposes. NY-ESO-1 is detected in 20 to 40% of melanomas. There is evidence that it is more frequent in advanced stages and that is associated with a worse prognosis. OBJECTIVES: to determine the frequency of NY-ESO-1 protein expression in cutaneous melanoma and to try to correlate it to Breslow index, melanoma histopathological aspects, including the tumor infiltrating lymphocytes, and patients morbi-mortality. METHODS: the present study is longitudinal of retrospective cohort. The research was carried on from August 2009 to October 2015. Eighty nine melanomas were selected from 87 patients in Oncology Outpatient Clinic, Dermatology Division, University of São Paulo and divided in 3 groups, such as: group 1: 34 melanomas with Breslow index <= 1,0 mm; group 2: 29 melanomas with Breslow index between 1,1 - 4,0 mm e group 3: 26 melanomas with Breslow index >= 4,0 mm. All specimens were reviewed for diagnostic, Breslow index and tumor infiltrating lymphocytes. After that, immunohistoquimical test for the presence of NY-ESO-1 antigen was performed in all 89 melanomas collected and in 20 nevi (11 dysplastic nevi and 9 dermal nevi) that were randomly chosen. By reviewing clinical charts, the following data was obtained: age, sex, skin phototype, site of the tumor, lymph node sentinel status, development of metastases and survival of the patients. The histological data analyzed was: histological melanoma type, presence of ulceration, grade of tumor infiltrating lymphocytes. In those melanomas that had tumor infiltrating lymphocytes, we performed immunohistoquimical tests for the presence of CD3+, CD8+, FoxP3+ and CD8+FoxP3+ (double positive) cells. RESULTS: antigen NY-ESO-1 was present in 19% of primary cutaneous melanomas and none of the 20 nevi. The expression of antigen NY-ESO-1 was statistically related to thicker melanomas. It presented also an inverse association with superficial spreading melanoma type compared to other subtypes. Tumor infiltrating lymphocytes of NY-ESO-1 positive melanomas had fewer CD3+ cells, that were isolated or arranged in small groups up to 5 cells, which was significantly different from tumors NY-ESO-1 negatives, with higher density of CD3+ cells, displayed in large groups of 6 or more cells. The expression of NY-ESO-1 protein was not associated to age, sex, phototype, site, ulceration, lymph node sentinel status, development of metastases and survival. CONCLUSIONS: A considerable amount of melanomas express NY-ESO-1, mainly thicker tumors. The fewer number of CD3+ cells in the tumor infiltrating lymphocytes, added to the fact of those cells being isolated or in small groups suggest that, although immunogenic, the expression of NY-ESO-1 antigen does not result in a efficient stimulus of the immune system to fight the tumor. The development of a vaccine to those patients may, in the future, enhance the roll of therapeutic possibilities for melanoma

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Cheryl, Lai Lai Chiang. "Assessing the potential of hypochlorous acid-oxidised allogeneic tumour cells as a source of antigens for dendritic cell-based immunotherapy of ovarian carcinoma and melanoma." Thesis, University College London (University of London), 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505526.

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Robert, i. Faja Lídia. "Inhibició de la via de la MAPK i efectes perifèrics de la inhibició dels moduladors immunes en melanoma metastàtic." Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/377432.

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El melanoma és el tumor cutani més maligne i la seva incidència ha experimentat un increment exponencial. En els últims anys, noves teràpies han aconseguit impactar positivament en la supervivència dels pacients amb melanoma metastàtic. A destacar, la teràpia dirigida envers aquells tumors portadors de la mutació BRAF V600, així mateix com l’alliberació de frens immunes amb inhibidors de modulació immunes (immune-checkpoints). Aquesta tesis està formada per dos articles centrats en els punt febles d’aquestes teràpies. El primer article defineix el repte de la resistència adquirida a inhibidors de BRAF i teràpies per aquells melanomes amb genotips orfes de tractament. La proposta d’un inhibidor d’ERK al final de la via de la proteïna quinasa activada pel mitogen (MAPK), proporciona activitat in vitro en un ventall de línies cel·lulars ben caracteritzades. El tractament combinat amb inhibidor de BRAF i inhibidor d’ERK aconsegueix arribar més lluny i aporta dades de sinèrgia contra la lluita envers la resistència adquirida. Per altra banda, el segon article es centra en el mecanisme subjacent a la baixa resposta i alta toxicitat associada al tractament amb els inhibidors d’antigen-4 de limfòcit T citotòxic (CTLA4). Fent ús de la seqüenciació de propera generació, hem pogut estudiar amb detall els canvis en la diversitat dels receptors de les cèl·lules T (TCR) i com aquests varien degut a l’exposició al tractament.
Melanoma is the most mortal skin cancer and its incidence has undergone exponential growth during at least the last 50 years. Recently, new therapies have demonstrated a positive impact in the survival of metastatic melanoma patients. Particularly worth highlighting are targeted therapy against those tumors harboring BRAF V600 mutation, or releasing the brakes from the immune system with immune-checkpoints. This thesis is comprised of two articles that focus on weak points of these therapies. The first paper defines the challenge of acquired resistance to BRAF inhibitors and therapies for melanomas treatment-orphan. ERK inhibitor blocks the mitogen-activated protein kinase (MAPK) and offers in vitro activity for a large group of very well defined cell lines. Combining BRAF inhibitor and ERK inhibitor shows synergistic activity when fighting against acquired resistance. The second article is focused on elucidating the mechanism associated with low responses and high toxicity related to treatment with cytotoxic T lymphocyte antigen-4 (CTLA4) blockade. Using next generation sequencing has provided insight into the changes in diversity for T cell receptor (TCR) and how these are affected by treatment.

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Mendonça, Samir Andrade. "Desenvolvimento e investigação da transferência gênica de p14ARF e interferon-beta em linhagens celulares de melanoma humano." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-07022019-093142/.

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O melanoma é um dos tipos de câncer de pele cuja frequência tem crescido nos últimos anos e apresentado elevada taxa de mortalidade, apesar de ter reduzida prevalência. Mesmo havendo um considerável avanço nas propostas terapêuticas nos últimos anos, ainda se vê necessário o desenvolvimento de novas abordagens, sendo a terapia gênica uma promissora possibilidade para tal. Utilizando vetores adenovirais com promotor responsivo à p53 (PGTx beta) para a transferência gênica de p19Arf (proteína supressora de tumor) e interferon-beta (citocina imunomodulatória) em células de melanoma murino com o gene Trp53 selvagem, o nosso grupo demonstrou previamente que a combinação dos dois genes, mas não o tratamento individual, promove efeito citotóxico sinérgico com a liberação de marcadores de morte imunogênica, in vitro; e significativa redução da progressão tumoral acompanhada de uma forte resposta imunológica de linfócitos T CD4+ e CD8+, células NK e neutrófilos contra desafios tumorais, in vivo. Porém, como a translação para modelos de melanomas humanos ainda estava em estágio inicial, ainda não haviam sido confirmamos se esses benefícios também seriam recapitulados. Observações inicias sugeriam que apenas a transferência gênica de interferon-beta seja suficiente para induzir morte celular em linhagens humanas portadoras de TP53 selvagem, sem ainda terem sido identificado o efeito da transferência de p14ARF e nem a necessidade de p53 endógeno para a resposta. Dessa forma, o presente projeto buscou avaliar os efeitos antitumorais provocados pela terapia gênica combinada de p14ARF e interferon-beta em modelos de melanoma humano utilizando linhagens com e sem a via da p53 integra. Para isso, foram utilizadas diferentes linhagens celulares com TP53 selvagem ou com distintas mutações e também foram construídos vetores adenovirais com o promotor constitutivo CMV, tornando assim possível a expressão dos transgenes de maneira independente do status do TP53 endógeno. O presente trabalho revelou que a transferência combinada do interferon-beta e p14ARF revelou vantagem quanto ao estímulo citotóxico e regulação negativa na dinâmica da população em ambas as linhagens UACC-62 e SK-Mel-29, independentemente do estado da via da p53. Na avaliação dos mecanismos de morte foi observado que ambas a linhagens apresentaram marcação positiva para marcadores da via da apoptose, porém com possível participação de outras modalidades de morte-celular, como a necrose, para a linhagem com o TP53 mutado (SK-Mel-29). Além disso, mostramos que os tratamentos potencialmente induzem vias de morte com caráter imunogênico pela secreção de ATP e exposição da calreticulina, sendo este último marcador mais significantemente observado mediante o tratamento combinado. Assim, recapitulamos o benefício observado em modelo murino para a transferência gênica do interferon-beta e p14ARF em modelo de melanoma humano, e investigamos marcadores importantes à translação da proposta terapêutica para o melanoma
Melanoma is one of the types of skin cancer whose frequency has grown in the last years and presents a high mortality rate, despite its low prevalence. Although there has been considerable progress in therapeutic proposals in recent years, it is still necessary to develop new approaches, being gene therapy a promising possibility for this. With the use of adenoviral vectors with a p53 responsive promoter (PGTx beta) for the gene transfer of p19Arf (tumor suppressor protein) and interferon-beta (immunomodulatory cytokine) in murine melanoma cells bearing wild-type Trp53 gene, our group previously demonstrated that the combination of the two genes, but not individual treatment, promotes a synergistic cytotoxic effect with the release of immunogenic death markers in vitro; and significant reduction of tumor progression with a strong immune response mediated by CD4+ and CD8+ T lymphocytes, NK cells and neutrophils in tumor challenges in vivo. However, as the translation for human melanoma models was still at an early stage, it still was not possible to confirm whether these benefits would also be recapitulated in a human model. Initial observations suggested that interferon-beta gene transfer is sufficient to induce cell death in wild-type TP53-bearing human melanoma cell lines, with the effect of p14ARF gene transfer and the role for endogenous p53 in this response yet to be investigated. Thus, the present work aimed to evaluate the antitumor effects induced upon the combined gene transfer of p14ARF and interferon-beta in human melanoma cell lines with and without a functional p53 pathway. For this, different cell lines bearing wild-type TP53 or with different mutations were used and adenoviral vectors with the constitutive CMV promoter were also constructed, making possible the expression of the transgenes independently of the endogenous TP53 status. The present work showed that the combined transfer of interferon-beta and p14ARF was advantageous in cytotoxic stimulation and negative regulation in population dynamics for both cell lines UACC-62 and SK-Mel-29, regardless of p53 pathway status. In the evaluation of the triggered cell death mechanisms it was observed that both cell lines presented positive markers of the apoptosis pathway, but with possible participation of other cell death mechanism, such as necrosis, for the mutated TP53 cell line SK-Mel-29. In addition, we showed that the treatments potentially induced cell death pathways with immunogenic features including the secretion of ATP and calreticulin exposure, being the latter marker more significantly presented after the combined treatment. Thus, we recapitulated the benefit observed in murine model for the gene transfer of interferon-beta and p14ARF in the model of human melanoma, and investigated important markers for the translation of the melanoma therapeutic proposal

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Le, Hanh. "AUGMENTATION OF T CELL EXPANSION FOR ADOPTIVE IMMUNOTHERAPY BY ALTERNATE GAMMA CHAIN CYTOKINES AND BY GEMCITABINE MEDIATED INHIBITION OF MYELOID DERIVED SUPPRESSOR CELLS." VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1563.

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Successful treatment of cancer with adoptive immunotherapy (AIT) is dependent on the ability to produce large numbers of tumor-specific, functional T cells. The purpose of this thesis is to explore ways in which T cell expansion could be augmented. We have focused on exploring alternate gamma chain cytokines as stimulators of T cell proliferation and differentiation in addition to investigating the potential usefulness of gemcitabine (GEM) in abrogating the immunosuppressive effects of myeloid derived suppressor cells (MDSCs). B16 melanoma sensitized draining lymph node cells that have been activated in vitro with bryostatin-1 and ionomycin (B/I) were expanded in either IL-7/15 or in IL-2. We found that IL-7/15 was superior to IL-2 in expanding T cells for AIT of pulmonary metastases. Expansion of antitumor T cells was also improved by suppressing accumulation of MDSCs in mice bearing 4T1 mammary carcinoma using GEM. GEM directly inhibits both 4T1 mammary carcinoma cells and MDSCs. Its inhibition of MDSCs rescued tolerant T cells, augmenting both expansion and response to tumor antigen.

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Moya, Plana Antoine. "Recherche de biomarqueurs pronostiques dans le mélanome muqueux non opérable et/ou métastatique : Régulation traductionnelle de SOX10 par l’hexokinase 2 et modulation de l'agressivité tumorale dans le mélanome cutané Prognostic Value and Therapeutic Implications of Nodal Involvement in Head and Neck Mucosal Melanoma Evaluation of the Efficacy of Immunotherapy for Non-Resectable Mucosal Melanoma Oncologic Outcomes, Prognostic Factor Analysis and Therapeutic Algorithm Evaluation of Head and Neck Mucosal Melanomas in France Mélanomes cutanés cervico-faciaux Prognostic 18F-FDG PET Biomarkers in Metastatic Mucosal and Cutaneous Melanoma Treated with Immune Checkpoint Inhibitors Targeting PD-1 and CTLA-4." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS069.

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Les mélanomes muqueux sont rares avec un potentiel métastatique important. L’immunothérapie est un traitement prometteur dans ce sous-type agressif de mélanome. L’analyse de biomarqueurs de réponse à une immunothérapie anti-PD1 chez 23 patients présentant un mélanome muqueux non opérable et/ou métastatique a montré que l’activation du complexe d’initiation de la traduction, eIF4F, était fortement prédictive de cette réponse. Cette activation a été mesurée par un test de proximité entre les sous-unités eIF4E et eIF4G. Les autres marqueurs admis, tels que l’expression tumorale de PD-L1 ou les caractéristiques de l’infiltrat lymphocytaire intra-tumoral, n’ont pas de valeur pronostique significative dans cette cohorte.La glycolyse anaérobie est la voie métabolique que la plupart des cellules tumorales privilégient lors de lacancérogenèse. Ce phénomène est appelé « effet Warburg ». Au cours de la mélanomagénèse, il existe un continuum entre l’expression croissante de l’hexokinase 2 (ou HK2, première enzyme de la glycolyse) et l’agressivité tumorale. Dans cette étude, nous avons montré que l’inhibition d’expression d’HK2 (par siARN) induisait, in vitro, une diminution majeure de la migration et de l’invasion tumorales indépendamment du métabolisme glucidique ou de l’expression initiale d’HK2. Par une technique de profilage des polysomes, nous avons observé que HK2 régulait la traduction de l’ARNm de SOX10, un facteur de transcription impliqué dans l’initiation et la progression du mélanome. Nous avons alors réalisé une immunoprécipitation de l’ARN après induction de liaisons protéine-ARN par du formaldéhyde, nous permettant ainsi de démontrer que la protéine HK2 se liait à l’ARNm de SOX10
Mucosal melanoma is a rare tumor with a high metastatic potential. Immunotherapy has promising results in this aggressive subtype of melanoma. In a cohort of 23 patients with non-resectable and/or metastatic mucosal melanoma who received anti-PD1 immunotherapy, we showed that the activation of the eukaryotic translation initiation complex, eIF4F, was a strong prognostic biomarker of response. This activation was assessed with a proximity ligation assay between eIF4E and eIF4G. The other biomarkers, such as the PD-L1 tumoral expression or the characteristics of tumor-infiltrating lymphocytes, had no prognostic value in this cohort.Aerobic glycolysis is usually the main metabolic pathway in tumor cells during cancerogenesis. This specificprocess is called “Warburg effect”. During melanomagenesis, we observed a positive correlation between the expression level of hexokinase 2 (HK2, first enzyme of glycolysis) and the tumor invasiveness. In this study, we showed that inhibition of HK2 expression (by siRNA) induced, in vitro, a major decrease of migration and invasion potential independently of the basal glycolytic metabolism or HK2 expression level in the cell lines. Moreover, performing a polysome profiling analysis, we demonstrated that HK2 was regulating the translation of SOX10 mRNA, a transcription factor involved in initiation and progression of melanoma. We, then, realized an RNA immunoprecipitation in formaldehyde and showed that HK2 was an RNA-binding protein, able to interact with the SOX10 mRNA

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Strioga, Marius. "Expression of biomarkers, representing immunosuppressive, cytotoxic or immunomodulating properties of CD8h T lymphocytes in the peripheral blood of patients with immunogenic cancer forms." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100702_105111-42651.

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The aim of the study was to evaluate the expression of immunosuppressive (FOXP3, NKG2A), and cytotoxic (perforin) or cytotoxic / immunomodulating (IFNγ) T-cell properties representing biomarkers in the peripheral blood CD8h T-cell population of patients with advanced renal cell carcinoma (RCC) or high risk cutaneous melanoma and healthy controls by multicolour flow cytometry. Determination of the percentage of functionally competing T-cell subsets (especially immunosuppressive) in the CD8hCD57+ T-cell subpopulation in future may serve as one of parameters enabling to assess the overall status of antitumor immune response and select cancer patients most suitable for antitumor immunotherapy while dismissing those to whom it would be ineffective or even harmful.
Darbo tikslas buvo įvertinti imunosupresines (FOXP3, NKG2A), citotoksines (perforin) bei citotoksines / imunomoduliuojančias (IFNγ) savybes atspindinčių žymenų raiškos skirtumus išplitusiu inkstų vėžiu ar didelės rizikos odos melanoma sergančių pacientų periferinio kraujo CD8h T limfocitų populiacijoje, lyginant su kontroline grupe. Skirtingas T limfocitų savybes atspindinčių žymenų raiška buvo tiriama tėkmės citometrijos būdu. Nustatyta, kad inkstų vėžiu ar odos melanoma sergančių pacientų periferiniame kraujyje Įvairių subpopuliacijų (ypač imunosupresinės) nuošimčio nustatymas CD8hCD57+ T limfocitų populiacijoje ateityje gali būti naudingas klinikinėje praktikoje, individualizuojant priešnavikinę imunoterapiją ir selektyviai parenkant tik tuos pacientus, kuriems imuninės sistemos aktyvinimas sukeltų navikinių ląstelių naikinimą, o ne dar labiau gilintų imunosupresiją.

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Strioga, Marius. "Imunosupresines, citotoksines bei imunomoduliuojančias savybes atspindinčių žymenų raiška imunogeniškomis vėžio formomis sergančių pacientų periferinio kraujo CD8h T limfocitų populiacijoje." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100702_105125-92547.

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Darbo tikslas buvo įvertinti imunosupresines (FOXP3, NKG2A), citotoksines (perforin) bei citotoksines / imunomoduliuojančias (IFNγ) savybes atspindinčių žymenų raiškos skirtumus išplitusiu inkstų vėžiu ar didelės rizikos odos melanoma sergančių pacientų periferinio kraujo CD8h T limfocitų populiacijoje, lyginant su kontroline grupe. Skirtingas T limfocitų savybes atspindinčių žymenų raiška buvo tiriama tėkmės citometrijos būdu. Nustatyta, kad inkstų vėžiu ar odos melanoma sergančių pacientų periferiniame kraujyje Įvairių subpopuliacijų (ypač imunosupresinės) nuošimčio nustatymas CD8hCD57+ T limfocitų populiacijoje ateityje gali būti naudingas klinikinėje praktikoje, individualizuojant priešnavikinę imunoterapiją ir selektyviai parenkant tik tuos pacientus, kuriems imuninės sistemos aktyvinimas sukeltų navikinių ląstelių naikinimą, o ne dar labiau gilintų imunosupresiją.
The aim of the study was to evaluate the expression of immunosuppressive (FOXP3, NKG2A), and cytotoxic (perforin) or cytotoxic / immunomodulating (IFNγ) T-cell properties representing biomarkers in the peripheral blood CD8h T-cell population of patients with advanced renal cell carcinoma (RCC) or high risk cutaneous melanoma and healthy controls by multicolour flow cytometry. Determination of the percentage of functionally competing T-cell subsets (especially immunosuppressive) in the CD8hCD57+ T-cell subpopulation in future may serve as one of parameters enabling to assess the overall status of antitumor immune response and select cancer patients most suitable for antitumor immunotherapy while dismissing those to whom it would be ineffective or even harmful.

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McCray, Andrea Nicole. "Electrogenetherapy of established B16 murine melanoma by using an expression plasmid for HIV-1 viral protein R." [Tampa, Fla] : University of South Florida, 2006. http://purl.fcla.edu/usf/dc/et/SFE0001758.

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Fregni, Giulia. "The role of human Natural Killer cells (NK) in anti-tumour immune responses." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T068/document.

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Les cellules Natural Killer (NK) sont des effecteurs cytotoxiques impliqués dans la réponse immune contre les infections et les tumeurs. Pendant ma thèse j’ai étudié la fonctionnalité des cellules NK humaines en réponse à des lignées cellulaires de carcinome rénal à cellules claires (RCC) et de mélanome métastatique, deux tumeurs immunogènes. Nos résultats montrent que certaines mutations de VHL augmentent la susceptibilité des lignées RCC à la lyse NK. La perte de fonction de VHL corrèle avec une expression membranaire diminuée des molécules HLA-I par les lignées RCC mutées pour VHL. Chez les patients atteints de mélanome métastatique de stade IV, nous avons décrit un phénotype particulier des NK sanguines (NKp46dim/NKG2Adim) qui leur confère une forte activité antitumorale. Après traitement des patients par chimiothérapie, la fonctionnalité NK était réduite et le phénotype modifié. Pour étudier les cellules NK infiltrant les mélanomes, nous avons mis au point des conditions expérimentales pour caractériser les cellules NK de ganglions métastatiques de patients de stade III. Nos résultats préliminaires montrent que, par rapport aux ganglions sains, les NK des ganglions métastatiques présentent un phénotype altéré et un potentiel fonctionnel diminué. Nos résultats suggèrent que d’une part l’immunogénicité dépendante des oncogènes et d’autre part les altérations NK induites par la tumeur et/ou par la chimiothérapie sont des facteurs importants à considérer dans le choix des protocoles d’immunothérapie basés sur les cellules NK
Natural Killer cells are cytotoxic lymphocytes involved in the immune response against tumours and infections. We investigated the NK-mediated functions in response to clear-cell renal cell carcinoma (RCC) and metastatic melanoma, two human immunogenic tumours. We showed that certain VHL mutations increased RCC cell susceptibility to NK lysis. VHL loss of function correlated with lower expression levels of membrane HLA-I molecules on VHL-mutated RCC and a decreased triggering of inhibitory NK receptors compared to RCC with a functional VHL. In stage IV melanoma patients, we showed that blood NK cells displayed a unique NKp46dim/NKG2Adim phenotype and high lytic potential towards melanoma cells. Following chemotherapy, NK cell function was reduced and the phenotype modulated. To study melanoma-infiltrating NK cells, we have set up experimental conditions to characterise NK cells in metastatic LNs from stage III melanoma patients. Our preliminary data show that, compared to normal LNs, NK cells from metastatic LNs are altered. Our findings suggest that oncogenic-dependent immunogenicity, tumour-associated NK alterations and chemotherapy are important factors that must be taken into account in the choice of immunotherapeutic protocols based on NK cells

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Lequeux, Audrey. "Impact du ciblage du domaine de liaison de HIF-1α avec HIF-1β sur le paysage immunitaire du mélanome Targeting HIF-1 Alpha Transcriptional Activity Drives Cytotoxic Immune Effector Cells into Melanoma and Improves Combination Immunotherapy Hijacker of the Antitumor Immune Response: Autophagy is Showing its Worst Facet Impact of Hypoxic Tumor Microenvironment and Tumor Cell Plasticity on The Expression of Immune Checkpoints Improving Cancer Immunotherapy by Targeting the Hypoxic Tumor Microenvironment: New Opportunities and Challenges." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL026.

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L’hypoxie est une caractéristique majeure des tumeurs solides et elle est capable d’induire un microenvironnement tumoral immunosuppressif. Nous avons étudié l’impact de l’inhibition du domaine de liaison de HIF-1α avec HIF-1β sur le paysage immunitaire du mélanome murin B16-F10. Le ciblage de ce domaine de liaison inhibe l’activité transcriptionnelle de HIF-1α dans les cellules B16-F10 in vitro. In vivo, l’inhibition de l’activité transcriptionnelle de HIF-1α dans le mélanome B16-F10 montre une diminution significative de la croissance tumorale et une amélioration consistante de la survie des souris. La croissance tumorale est restaurée dans les souris immunodéficientes, soulignant l’importance du système immunitaire dans le contrôle de la croissance du mélanome. L’étude du phénotype des cellules immunitaires intra-tumorales révèle une augmentation de l’infiltration des cellules Natural Killer (NK), des lymphocytes T CD4+, des T régulateurs, des macrophages de type M1 et M2 et des cellules dendritiques lorsque l’activité transcriptionnelle de HIF-1α est inhibée. La déplétion de cellules NK dans notre modèle expérimental restaure la croissance tumorale, soulignant le rôle des NK dans la surveillance du mélanome B16-F10. Le changement du paysage immunitaire observé dans notre modèle corrèle également avec une modification du réseau de cytokines caractérisé par une nette augmentation de la sécrétion de CCL5 et de CCL2. En conclusion, cette étude met en évidence le rôle de HIF-1α dans le contrôle de la croissance et le remodelage du paysage immunitaire du mélanome B16-F10. Elle indique la possibilité de combiner un inhibiteur de HIF-1α avec une immunothérapie basée sur le blocage des points de contrôle immunitaire pour étendre leur efficacité et leur bénéfice thérapeutiques à un plus grand nombre de patients cancéreux
Hypoxia is a major feature of solid tumors and is able to induce a tumor immunosuppressive microenvironment. Here, we investigated the impact of inhibiting of the binding domain of HIF-1α to HIF-1β on the immune landscape of B16-F10 melanoma. Targeting this binding domain inhibits the transcriptional activity of HIF-1α in B16-F10 cells in vitro. In vivo, inhibiting the transcriptional activity of HIF-1α in B16-F10 melanoma shows a significant decrease in tumor growth and a consistent improvement in mice survival. Tumor growth is restored in immunodeficient mice, highlighting the critical role of the immune system in controlling melanoma growth. The phenotyping of intra-melanoma immune cells reveals an increase in Natural Killer (NK), CD4+ T cells, regulatory T cells, M1 and M2 macrophages and dendritic cells. NK depletion restores tumor growth in our experimental model, highlighting the role of NK cells in melanoma surveillance. The alteration of the immune landscape that we observed also correlates with a clear increase of secreted CCL5 and CCL2. In conclusion, this study highlights the role of HIF-1α in controlling the growth and the immune landscape of B16-F10 melanoma. It indicates the opportunity of combining HIF-1α inhibitors with immune checkpoint blockade to extend immune checkpoint blockade efficiency and therapeutic benefit to a larger number of cancer patients

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TESSIER, MARIE-HELENE. "Immunotherapie des melanomes metastatiques par til (lymphocytes infiltrant la tumeur) : a propos de six cas." Nantes, 1993. http://www.theses.fr/1993NANT266M.

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40

Azzarone, Bruno. "Analyse des interactions entre l'interleukine 2, l'interleukine 15 et les cellules humaines fibroblastiques ou issues de melanome." Paris 11, 1997. http://www.theses.fr/1997PA114821.

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41

RODRIGUES, DANIELLE B. "Terapia antiangiogênica de tumores utilizando células produtoras de endostatina encapsuladas em sipositivos de imunoisolamento." reponame:Repositório Institucional do IPEN, 2008. http://repositorio.ipen.br:8080/xmlui/handle/123456789/11711.

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Dissertacao (Mestrado)
IPEN/D
Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

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42

Han, Daishu. "Etude de la regulation de l'expression du systeme il-2/il-2r dans les fibroblastes de souris et les cellules de melanome humain." Paris 11, 1995. http://www.theses.fr/1995PA114810.

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43

Auroy, Catherine. "Dysfonctionnements thyroi͏̈diens chez des patients atteints de mélanome malin et traités par chimioimmunothérapie." Paris 5, 1994. http://www.theses.fr/1994PA05P258.

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44

Zhu, Chaobin. "Rôle du facteur de croissance IGF-1 (Insulin-Like Growth Factor-1) sur la progression tumorale invasive et métastatique du mélanome : approches anti-tumorales basées sur l'inhibition du facteur IGF-1." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T012.

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Parmi les cancers cutanés, le mélanome métastatique est le moins fréquent (5 à 7%) mais le plus meurtrier par sa forte résistante aux thérapies conventionnelles. Bien qu'immunogène, aucun traitement efficace n'existe actuellement pour traiter ce cancer, ce qui fait qu'il est urgent de trouver de nouvelles cibles thérapeutiques. Dans ce contexte, nous avons évalué si l'Insulin-Like Growth Factor-1 (IGF-1) pouvait représenter une cible d'intérêt thérapeutique dans le mélanome en inhibant l'expression du facteur IGF-1, à l'aide d'un épisome antisens, dans deux modèles cellulaires : des cellules de mélanome primaire B16-F0 et métastatique B16-F10 (cellules appelées B16-F0mod et B16-F10mod lorsque l'expression d’IGF-1 est inhibée).Dans des modèles expérimentaux in vivo, nos résultats montrent que la réduction d'expression d'IGF-1 induit une diminution de la tumorigénicité des cellules de mélanome, en générant des tumeurs sous-cutanées plus petites (B16-F0 et B16-F10 dans les souris C57BL/6) et en inhibant totalement (souris C57BL/6) ou fortement (souris NSG) la capacité des B16-F10 à former des métastases pulmonaires. Nous avons cherché à comprendre si cette perte de tumorigénicité, suite à l'inhibition du facteur IGF-1, était due à une modification de l'immunogénicité/antigénicité des cellules tumorales et/ou à une modification du potentiel tumorigène intrinsèque des cellules tumorales métastatiques.1/ L’immunisation de souris C57BL/6 à l'aide de cellules B16-F0mod induit la formation d’effecteurs humoraux lytiques en présence de complément dirigés contre la lignée parentale, mais également d’effecteurs cellulaires CD8+ capables d’induire la lyse des cellules tumorales in vitro et d’inhiber la croissance tumorale in vivo. Bien que l'analyse des voies humorale et cellulaire n'ait pas permis de démontrer les mécanismes IGF-1-dépendants mis en jeu avec les cellules B16-F10, l'immunisation des souris C57BL/6 à l'aide de cellules B16- F0mod conduit à une inhibition de la croissance des tumeurs sous-cutanées et du nombre de métastases pulmonaires, confirmant l'implication du facteur IGF-1 dans des mécanismes d'échappement tumoral au système immunitaire.2/ Nos résultats montrent par ailleurs que le facteur IGF-1 joue un rôle direct sur le potentiel tumorigène intrinsèque des cellules tumorales. Outre son action sur la prolifération des cellules tumorales, IGF-1 est impliqué dans le processus de transition épithélio-mésenchymateuse (augmentation des marqueurs N-cadhérine, vimentine, CD44 et CD29), favorisant le maintien de populations tumorales présentant un caractère souche (Sox2, Oct3/4, CD44, CD24, activité ALDH, side population, capacité à former des sphéroïdes). Par ce mécanisme, IGF-1 favorise à la fois les propriétés migratoires et d'efflux de drogues, comme la mitoxantrone, par les transporteurs ABC, qui explique en partie la forte résistance des mélanomes aux thérapies conventionnelles.Ces travaux montrent que l’inhibition de la voie IGF1/IGF1-R pourrait être une bonne stratégie pour le développement de traitements anti-tumoraux contre le mélanome. Outre le développement de stratégies d'immunothérapie, le blocage de la voie IGF-1 permettrait également de sensibiliser les cellules de mélanome aux traitements conventionnels et de diminuer le potentiel métastatique des cellules tumorales
Metastatic melanoma is the least common (5-7 %), but is responsible for most skin cancer deaths by its strong resistance to conventional anti-cancer treatments. Although immunogen, no effective treatment currently exists against this aggressive form, making urgent to find new therapeutic targets. In this context, we assessed whether the Insulin-like Growth Factor-1 (IGF-1) could represent a target of therapeutic interest in melanoma inhibiting the expression of IGF-1 by means of an episome-based vector encoding antisense IGF-1, in two cellular models: primary melanoma cells B16-F0 and metastatic B16-F10 (designated B16-F0mod and B16-F10mod when IGF-1 expression is inhibited).In experimental models in vivo, our results show that the reduction of IGF-1 expression induced a decrease of the melanoma cells tumorigenicity, generating smaller tumors under the skin (B16-F0 and B16-F10 in the C57BL/6 mice) and inhibiting totally (C57BL/6) or strongly (NSG mice) the developpment of B16-F10 lung metastases. We sought to understand whether this loss of tumorigenicity, following IGF-1 inhibition, was due to a change of immunogenicity/antigenicity of tumor cells and/or to intrinsic tumorigenic potential modification of metastatic tumor cells.1 / Immunization of mice C57BL/6 mice with B16-F0mod cells induces the formation of humoral lytic effectors in the presence of complement against the parental line, but also CD8+ effector cells capable of inducing tumor cells lysis in vitro and inhibiting tumor growth in vivo. Although the analysis of humoral and cellular pathways did not demonstrate IGF-1- dependent mechanisms involved in B16-F10 cells, immunization of C57BL/6 mice with B16 cells F0mod leads to skin tumor growth inhibition and a reduction in pulmonary metastases number, confirming the involvement of IGF-1 factor in tumor escape mechanisms of the immune system.2 / Our results also show that IGF-1 plays a direct role in the intrinsic tumorigenic potential of tumor cells. In addition to its effect on tumor cells proliferation, IGF-1 is involved in epithelial-mesenchymal transition (increased N-cadherin, vimentin, CD44 and CD29 markers), promoting the maintenance of tumor populations with stemness properties (Sox2, Oct3/4, CD44, CD24, ALDH activity side-population and ability to form spheroids). By this mechanism, IGF-1 promotes both migration properties and drugs efflux such as mitoxantrone, via ABC transporters, which partly explains the strong resistance of melanoma to conventional therapies.This work shows that the inhibition of IGF1/IGF1-R pathway might be a good strategy for the development of anti-tumor treatments against melanoma. In addition to developing immunotherapy strategies, blocking the IGF-1 pathway would also sensitize melanoma cells to conventional therapy and decrease the metastatic potential of tumor cells

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Silva, Inês Esteves Domingues Pires da. "Immunotherapy in melanoma : the role of nk cells." Doctoral thesis, 2016. http://hdl.handle.net/10362/18520.

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RESUMO: O melanoma é o quinto tumor maligno mais comum nos homens (sétimo nas mulheres) e a sua incidência está a aumentar mais rapidamente do que a de qualquer outro cancro. É o tipo de cancro cutâneo mais agressivo; corresponde a apenas 2% de todos os cancros de pele, mas é responsável por mais de 70% das mortes causadas pelo cancro cutâneo. O melanoma responde mal à terapia sistémica e tem mau prognóstico nos doentes com metástases à distância, com uma taxa de sobrevivência global aos 2 anos que varia entre os 18 e os 40%. No contexto do cancro identificamos duas respostas imunológicas opostas: uma resposta aguda anti-tumoral com predomínio de células Th1 podendo, consequentemente, levar a uma reacção auto-imune; e uma resposta inflamatória pró-tumoral, caracterizada por uma tolerância imunológica através de mecanismos imunossupressores. Durante a progressão do tumor verifica-se um desequilíbrio com um predomínio da resposta inflamatória pró-tumoral e disfunção das células anti-tumorais Th1. O conceito de "exaustão dos linfócitos T” tem sido desenvolvido nos últimos anos e pode explicar a disfunção das células Th1. Este conceito de "exaustão dos linfócitos T", consequência do microambiente tumoral ou de outros factores, foi descrita pela primeira vez em doenças infecciosas crónicas e mais recentemente em diferentes tipos de cancro, em particular no melanoma. Este fenótipo é caracterizado pela perda progressiva da capacidade de proliferação, do potencial citotóxico e da capacidade de produzir interleucina 2 (IL-2). A “exaustão dos linfócitos T” no contexto do cancro metastático tem sido reforçado pelo recente sucesso de imunoterapias dirigidas aos marcadores de exaustão expressados pelos linfócitos T, incluindo o CTLA-4 e o PD-1, em doentes com melanoma avançado. No entanto, o fenótipo e a função das NK em diferentes fases da progressão do tumor e a sua relação com fatores de prognóstico ainda é desconhecida. As células NK pertencem ao sistema imune inato e têm um papel importante na resposta antitumoral. A função destas células depende do equilíbrio entre os receptores de activação e de inibição, e da expressão dos respectivos ligandos no microambiente tumoral. O Tim-3, outro marcador de exaustão dos linfócitos T juntamente com o CTLA-4 e o PD-1, comporta-se como um receptor inibitório nos linfócitos T e tem um papel fundamental para a manutenção da tolerância imunológica. O Tim-3 também é expresso nas células NK, no entanto o seu papel na modulação da função destas células permanece pouco claro, em particular no contexto do cancro. Os objetivos deste estudo foram: caracterizar o fenótipo e a função das células NK em doentes com melanoma; identificar moléculas, que possam estar envolvidas no mecanismo da exaustão das células NK, como potenciais marcadores de prognóstico no melanoma; definir o papel do Tim-3 expresso nas células NK de doentes com melanoma avançado; e estudar o efeito do bloqueio de checkpoints imunológicos no fenótipo e função das células NK no contexto dos doentes com melanoma avançado. Os nossos dados mostraram que as células NK de doentes com melanoma avançado exibem um fenótipo de exaustão imunológica que é caracterizado por uma expressão aumentada dos receptores inibitórios KIR3DL1 e KIR2DL3, por uma expressão diminuida dos receptores de activação NKG2D, NKp46 e DNAM-1, por uma resposta deficiente à estimulação com IL-2, por uma regulação negativa dos fatores de transcrição T-bet e Eomes, e por um défice de função (citotoxicidade, produção de IFN-γ e proliferação). As células NK adquirem gradualmente este fenótipo de exaustão imunológica à medida que a doença avança dos estadios iniciais (estadios I e II) para estadios mais avançados (estadios III e IV). Curiosamente, este fenótipo de exaustão das células NK está associado as parâmetros clinico-patológicos com valor prognóstico conhecido, como a espessura e a presença/ausência de metástases (regionais e à distância). Além disso, níveis elevados de MICA solúvel (ligando do receptor NKG2D) no plasma podem estar envolvidos no mecanismo de exaustão das células NK e identificam doentes com sobrevivência global e tempo de livre de doença mais curtos. Neste trabalho também identificamos o Tim-3 como um receptor inibitório e com uma expressão aumentada nas células NK de doentes com melanoma avançado, e que desempenha um papel chave no fenótipo de exaustão destas células. Mais importante, mostramos ainda que o bloqueio do receptor Tim-3 consegue reveter, em parte, este fenótipo de exaustão, com um aumento da citotoxicidade em 20%, da produção de IFN-γ em 15% e da proliferação em 60%. Finalmente, caracterizamos o efeito do ipilimumab (anti-CTLA-4) no fenótipo de exaustão das células NK de doentes com melanoma avançado. Notavelmente, as células NK de doentesrespondedores ao tratamento com ipilimumab apresentaram níveis mais elevados de IL-2R e, por conseguinte, maior citotoxicidade em resposta à estimulação com IL-2. Estes dados abrem caminho para novas estratégias terapêuticas com base nas células NK, incluindo o bloqueio do receptor Tim-3 no contexto de melanoma. Além disso, uma melhor compreensão do mecanismo subjacente à exaustão das células NK irá definir novos marcadores de prognóstico e estratégias terapêuticas.
ABSTRACT: Melanoma is the fifth most common cancer in men (seventh in women) and its incidence is increasing more rapidly than that of any other malignancy. It is the most aggressive type of skin cancer; although it accounts for 2% of all skin cancers it leads to more than 70% of their deaths. In fact, melanoma responds poorly to systemic therapy and the overall prognosis of patients with distant metastasized melanoma remains poor; the 2-year overall survival rate ranges from 18 to 40%. In the context of cancer two opposite immune responses exist: an acute T helper (Th) 1 antitumoral response that requires a substantial autoimmune attack; and a pro-tumorigenic inflammatory response, characterized by an immune tolerance via active immunosuppressive mechanisms. During tumor progression there is an imbalance with a stronger pro-tumorigenic inflammatory response, while the anti-tumoral Th1 cells display a dysfunctional phenotype. The new concept of “T cell exhaustion”, that has been developped in the past few years, can explain T cell dysfunction. This “T cell exhaustion”, either caused by environmental influence or other factors, was first described in chronic infectious diseases and more recently in different types of cancer, particularly in melanoma. This phenotype is characterized by early loss of proliferative capacity, cytotoxic potential, and the ability to produce interleukin (IL)-2. The concept of T cell exhaustion in the context of metastatic cancer has been reinforced by the recent success of immunotherapies targeting the exhaustion markers cytotoxic Tlymphocyte- associated protein 4 (CTLA-4) and programmed (cell) death 1 (PD-1) in advanced melanoma. However, the phenotype and function of natural killer (NK) cells in different phases of tumor progression and their relationship with prognostic factors is still unknown. NK cells are innate immune cells, prone to target tumor cells, whose function depends on the balance between activating and inhibitory receptors, and on the expression of the respective ligands in their microenvironment. T cell immunoglobulin domain and mucin domain 3 (Tim- 3), another T cell exhaustion marker along with CTLA-4 and PD-1, behaves as an inhibitory receptor in T cells and is key in the maintenance of immune tolerance. Tim-3 is also expressed in NK cells; however its role in modulating the function of these innate effector cells remains unclear, particularly in human disease. The aims of this study were: to characterize the phenotype and function of NK cells from melanoma patients; to identify potential players in the mechanism of NK cell exhaustion as prognostic markers; to define the role of Tim-3 expression in NK cells from advanced melanoma patients; and to study the effect of checkpoint blockade in NK cell phenotype and function in the context of advanced melanoma patients. Our data showed that NK cells from patients with advanced melanoma display an exhausted phenotype that is characterized by upregulation of inhibitory receptors (Killer cell Immunoglobulin-like receptor 3DL1 and 2DL3 - KIR3DL1 and KIR2DL3, respectively), downregulation of activating receptors (natural-killer group 2D (NKG2D), natural killer p46 (NKp46) and DNAX accessory molecule-1 (DNAM-1)), unresponsiveness to IL-2 stimulation, downregulation of the transcription factors T-box (T-bet) and eomesodermin (Eomes), and defective function. The latter includes the main NK cell functions, cytotoxicity, interferon gamma (IFN-γ) production and proliferation. NK cells acquire this exhausted phenotype gradually as disease advances from early (stages I and II) to later stages (stages III and IV). Moreover, the exhaustion of NK cells is associated with clinicopathological parameters that have known prognostic value, such as thickness and presence/absence of metastases (regional and distant). In addition, high serum levels of soluble MHC class I chain-related genes A (sMICA), an NKG2D ligand (NKG2DL) that may be involved in the mechanism of NK cell exhaustion, identify patients with shorter diseasefree and overall survival. We also identified Tim-3 as an inhibitory receptor over-expressed in NK cells from advanced melanoma patients that plays a key role in the exhausted phenotype of these cells. Significantly, we demonstrated that Tim-3 blockade partially reversed this exhausted phenotype. Therefore, in average, it was possible to enhance cytotoxicity by 20%, IFNγ production by 15% and proliferation by 60%. Finally, we characterized the effect of ipilimumab (anti-CTLA-4) on exhausted NK cells from advanced melanoma patients. Remarkably, NK cells from responders to ipilimumab treatment have higher levels of IL-2 receptor (IL-2R), and consequently, are more responsive to IL-2 stimulation and more cytotoxic.These data open exciting avenues for new NK cell-based therapies, including targeting Tim-3 in the context of melanoma. Moreover, a better understanding of the mechanism behind NK cell exhaustion will help defining new prognostic markers and therapeutic strategies.

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Moreira, Ana Rita Sampaio. "Anti-PD-1 Immunotherapy in Advanced Metastatic Melanoma." Master's thesis, 2019. http://hdl.handle.net/10316/88302.

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Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia
A imunoterapia com inibidores do checkpoint imunitário, como os fármacos anti-PD-1, é uma área em crescente desenvolvimento devido à sua eficácia terapêutica e às vantagens no tratamento do melanoma metastático avançado. De facto, a imunoterapia tem sido alvo de vários estudos recentes em diversos tipos de cancro, nomeadamente no melanoma, uma ameaça crescente a nível mundial. As taxas de incidência do melanoma estão a aumentar: em 2018 na Europa, foi considerado o quinto e oitavo cancro com maior número de novos casos estimados entre mulheres e homens, respetivamente, constituindo uma ameaça à saúde em todo o mundo. A contribuir para a incidência crescente deste cancro estão as alterações climáticas, em particular o aquecimento global do século passado, que veio aumentar a tendência para passar mais tempo ao ar livre e, consequentemente, a exposição à luz solar e radiação ultravioleta. De entre os fatores de risco mais relevantes para o melanoma, o aumento da radiação ultravioleta devido à destruição da camada do ozono constitui um dos principais responsáveis pelo número crescente de novos casos. Os agentes anti-PD-1, tais como o Nivolumab e o Pembrolizumab, permitem um tratamento mais eficaz, aumentando a duração das respostas à terapia e prolongando a sobrevida do paciente. No entanto, estudos recentes de segurança e tolerabilidade afirmaram que, embora estes fármacos apresentem menos efeitos adversos e toxicidade, podem ser responsáveis por eventos adversos específicos mediados por autoimunidade. No geral, a imunoterapia com agentes anti-PD-1 representa uma área altamente promissora no tratamento de alguns tipos de cancro, tal como o melanoma.
Immunotherapy with immune checkpoint inhibitors, such as anti-PD-1 drugs, is an area in increasing development for its efficacy and advantages in the treatment of advanced metastatic melanoma. In fact, immunotherapy has been the target of several and recent studies in different types of cancer, namely in melanoma, a globally growing threat. The incident rates for melanoma are increasing: in 2018 in Europe, it was the fifth and eighth cancer with more estimated new cases among females and males, respectively, posing a major health threat worldwide. Contributing to the increasing incidence of this cancer is climate change, particularly global warming of the past century, which has increased the tendency to spend more time outdoors and, consequently, the exposure to sunlight and ultraviolet radiation. Among the most relevant risk factors for melanoma, the increase in ultraviolet radiation due to ozone layer depletion is one of the main factors responsible for the incidence of new cases. Anti-PD-1 agents like Nivolumab and Pembrolizumab allow a more effective treatment, increasing the duration of the responses to the therapy and prolonging the survival of the patient. However, recent studies about safety and tolerability have stated that, although these drugs present less adverse effects and toxicity, those may lead to specific autoimmune-mediated adverse events. Overall, immunotherapy with anti-PD-1 agents represents a highly promising area in the treatment of some types of cancer such as melanoma.

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Jiang, Shiau-Yi, and 蔣孝儀. "Establishment of melanoma antigen-specific cancer immunotherapy and evaluation of antitumor effect in a murine melanoma model." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/83000625871549590668.

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碩士
國立中興大學
獸醫學系暨研究所
98
Melanoma cells selectively express a number of differentiation antigens including melan-A, gp100, and tyrosinase that can serve as targets for an immunotherapy strategy. The aim of our study was to construct a melanoma specific antigen expression plasmid as an immunotherapy for canine melanoma. A multiepitope sequence, which modified from a previous study, was generated by annealing of a set of 8 primers by PCR reaction. A plasmid in which expression of the multiepitope sequence of melanoma antigens or fused with the GFP (green fluorescence protein) was constructed. The transient expression of multiepitope-GFP in eukaryotic cells (HEK-293T) was confirmed by fluorescent microscopy and western blot analysis. Evaluation of safety and acute toxicity was performed, and adverse effect was not significant in C57BL6/J mice intramuscularly injected with multiepitope plasmid at three different doses (5, 50, 250 μg) after 7 days of observation. Furthermore, a melanoma model was successfully established in C57BL/6J mice and the therapeutic effect of the plasmid was evaluated on these tumor bearing mice. The growth of tumor volume in the therapeutic group was significant inhibited than the mock group (＊p<0.05) and control group (＊p<0.05) on day 24. The multiepitope plasmid might be a potential therapy to regress the melanoma or improve survival time of patients and further investigation of multiepitope plasmid on canine melanoma is necessary.

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Ramos, Laura Soares. "Terapêutica neoadjuvante do melanoma." Master's thesis, 2021. http://hdl.handle.net/10316/98468.

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Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
O melanoma cutâneo é o tumor cutâneo com maior taxa de mortalidade. De facto, o diagnóstico de doença localmente avançada está associado a pior prognóstico, com elevadas taxas de recorrência, mesmo perante a aplicação do tratamento preconizado. A introdução de terapêutica neoadjuvante poderá não só melhorar a abordagem cirúrgica, tida como curativa, como também traduzir-se em benefício para a sobrevivência destes doentes. A fim de perceber quais as terapêuticas que têm vindo a ser estudadas na abordagem neoadjuvante e o seu impacto no prognóstico, procedeu-se à revisão da literatura relevante, disponível nas bases de dados Pubmed e Web of Science, de 2015 a 2020. É evidente o desenvolvimento da terapia neoadjuvante. Iniciou-se pelo estudo da quimioterapia, da bioquimioterapia e pela utilização de doses elevadas de interferão α. A identificação de potenciais alvos moleculares terapêuticos fez considerar novas terapêuticas, como a imunoterapia (baseada na inibição de checkpoints CTLA-4 e PD-1) e a terapia dirigida (nos melanomas com gene BRAF mutado). Verificou-se existir uma melhoria na sobrevivência dos doentes com melanoma localmente avançado possivelmente ressecável, especialmente com a utilização das novas terapêuticas. No entanto, a evidência disponível ainda não é suficiente para a definição de um regime terapêutico neoadjuvante efetivo e seguro.
Cutaneous melanoma has the highest mortality rate of skin cancers. In fact, the diagnosis of locally advanced melanoma is associated with worse prognosis and with high recurrence rates, even after recommended treatment. The introduction of neoadjuvant therapy might improve surgical approach, regarded as curative, and translate into benefit for those patient’s survival. To understand which therapies have been studied for neoadjuvant approach and their impact on prognosis, the available relevant literature on Pubmed and Web of Science, from 2015 to 2020, was reviewed. It is clear the development of neoadjuvant therapies. It began on chemotherapy, biochemotherapy and high doses of interferon α. The identification of potential therapeutic molecular targets did consider new therapies, such as immunotherapy (based on inhibition of CTLA-4 and PD-1 checkpoints) and target therapy (for BRAF-mutated melanoma). There was an improvement in patient’s survival with resectable stage III melanoma, especially with the new therapies. However, the available evidence is still not enough to define an effective and safe neoadjuvant therapeutic regimen.

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Davey, Ryan James. "Examining the expression of nucleotide excision repair genes in melanoma tumours." Thesis, 2017. http://hdl.handle.net/1959.13/1337722.

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Research Doctorate - Doctor of Philosophy (PhD)
Melanoma is an aggressive form of cancer characterised by poor prognosis and resistance to treatment. Despite recent advances in melanoma treatment, patient outcomes continue to be underwhelming. After these new therapies showed initial promise; resistance and poor duration of response have limited their effectiveness as monotherapies. We are currently at the forefront of a wave of research into the underlying mechanisms of melanoma characteristics. It is now understood that for effective treatments to be developed, we must have a greater understanding of the genetic mechanisms of melanoma’s treatment resistance and abnormally aggressive phenotype. Ultraviolet radiation (UVR) has continually been intrinsically linked to melanoma development. In addition to this, resistance to traditional DNA-damaging chemotherapy drugs such as cisplatin remains a hallmark of melanoma cells. Nucleotide excision repair (NER) orchestrates the repair of helix distorting DNA damage, induced by both ultraviolet radiation (UVR) and cisplatin. There is evidence that the global genome repair (GGR) arm of NER is dysfunctional in melanoma and it is known to have limited induction in melanoma cell lines after cisplatin treatment. To further investigate the links between NER and melanoma, we examined the expression of multiple key genes involved in the NER pathway function and regulation, in a cohort of melanoma tumours. The expression of these transcripts was then compared to clinical parameters. In addition to this, expression of GGR damage recognition protein, XPC, was also quantified in melanoma tumours.

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Kojzarová, Martina. "Příprava chimerických VLP myšího polyomaviru nesoucích epitopy maligního melanomu." Master's thesis, 2011. http://www.nusl.cz/ntk/nusl-312453.

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Major capside protein of Polyomaviridae family viruses is able to selfassemble into virus-like particle (VLP) even without the presence of minor proteins, bind exogenous DNA non-specifically and recognise the receptor on the cellular surface. These characteristics determine its use as vector in gene therapy or immunotherapy. It was discovered before that MPyV VLPs significantly stimulate immune system and have strong adjuvant effect. Chimeric VLP derived from mouse polyomavirus carrying exogenous antigene or epitop is supposed to elicit specifically targeted immune response after immunisation. The main obstacle is choice of immunogene that is strong enough to cause adequate immune response. The goal of this thesis was to construct chimeric particles carrying epitop of malignant melanoma, one of the most immunogenic tumours, on their surface, using methods of genetic engineering. For future research of particle's immunogenic properties three types of particles were developed - particles with human and mouse melanoma epitopes, respectively and control particles with ovalbumine epitop. For the purpose of production of chimeric protein was used baculovirus expression system. It was verified then, with the use of electron microscopy, that introduction of tumour antigen into one of surface loops of VP1...

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Dissertations / Theses on the topic 'Melanoma – Immunotherapy'

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