Дисертації з теми "Cancer immunotherapies"
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Murray, Abner A. "Plant Virus Nanoparticle In Situ Cancer Immunotherapies." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1532370850718292.
Повний текст джерелаMoynihan, Kelly D. (Kelly Dare). "Engineering immunity : enhancing T Cell vaccines and combination immunotherapies for the treatment of cancer." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/113960.
Повний текст джерелаCataloged from PDF version of thesis.
Includes bibliographical references (pages 127-140).
Checkpoint blockade with antibodies against CTLA-4 or PD-1 has demonstrated that an endogenous adaptive immune response can be stimulated to elicit durable tumor regressions in metastatic cancer, but these dramatic responses are confined to a minority of patients¹-³. This outcome is likely due in part to the complex network of immunosuppressive pathways present in advanced tumors, which necessitates the development of novel therapeutics and combination immunotherapies to generate a counter-directed network of pro-immunity signals⁴-⁸. In Chapters 2 and 3 of this thesis, we describe methods for enhancing T cell priming against tumor antigens via covalent modification of molecular vaccines to enhance lymphatic drainage, serum stability, or cytosolic access to improve presentation on MHC class I. In Chapter 4, we demonstrate a combination immunotherapy that recruits a diverse set of innate and adaptive effector cells, enabling robust elimination of large tumor burdens that to my knowledge have not previously been curable by treatments relying on endogenous immunity. Maximal anti-tumor efficacy required four components: a tumor antigen targeting antibody, an extended half-life IL-2⁹, anti-ƯPD-1, and a powerful T-cell vaccine¹⁰. This combination elicited durable cures in a majority of animals, formed immunological memory in multiple transplanted tumor models, and induced sustained tumor regression in an autochthonous BRraf[superscript V600E]/Pten[superscript -/-] melanoma model. Finally, in Chapter 5, we show preliminary data on combination immunotherapies used to treat antigenically heterogeneous tumors. Taken together, these data define design criteria for enhancing the immunogenicity of molecular vaccines and elucidate essential characteristics of combination immunotherapies capable of curing a majority of tumors in experimental settings typically viewed as intractable.
"During my doctorate by the John and Fanny Hertz Foundation Fellowship (specifically the Wilson Talley Hertz Fellowship), the NSF Graduate Research Fellowship Program, and the Siebel Scholarship"--Page 141. "This thesis work was supported in part by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the US National Institutes of Health (NIH) grant CA174795, the Bridge Project partnership between the Koch Institute for Integrative Cancer Research and the Dana Farber-Harvard Cancer Center (DF-HCC), the V Foundation, the Ragon Institute, and the Howard Hughes Medical Institute"--Page 141.
by Kelly D. Moynihan.
Ph. D.
Natarajan, Gayathri. "THE USE OF A TEC KINASE INHIBITOR, IBRUTINIB, FOR THE DEVELOPMENT OF IMMUNOTHERAPIES AGAINST CANCER AND LEISHMANIASIS." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461200133.
Повний текст джерелаMustapha, Rami. "Evaluation of novel anti-tumoral strategies using peptide or monoclonal antibody immunotherapies." Thesis, Lille 1, 2016. http://www.theses.fr/2016LIL10198/document.
Повний текст джерелаThe immune system can recognize and eliminate cancer cells but is held back by inhibitory factors such as Regulatory T cells (Tregs). Gal-9 is a β-galactoside binding lectin with immunosuppressive capabilities expressed by cancer cells and immune cells including Tregs. NPC is a malignant epithelial cancer which is almost always associated with Epstein Bar Virus (EBV) and expresses several viral proteins. Numerous vaccines targeting different EBV peptides had limited success in clinical trials. First part: we aimed to confirm the role of Gal-9 in human Treg function. Then we tested the capabilities of an anti-human-Gal-9 antibody (mAb) to block Gal-9 suppressive function and its effect on Treg function and the anti-tumoral response. We proved that Gal-9 is expressed and secreted by Tregs at a high level. The mAb antagonized the function of recombinant rGal-9 on PBMCs. Moreover, the mAb inhibited the immuno-suppressive function of Tregs. Gal-9 blocking in PBMC culture promoted a Th1 response without inducing toxicity. We used the mAb to inhibit hNPC derived exosomes. In-vivo, the mAb limited the growth of hNPC tumors in humanized SCID mice. Second part: CD4+ T cell response is essential in managing NPC. The use of a CD4+ T cell response inducing peptide cocktail vaccination strategy was tested here. 6 HLA II promiscuous peptides derived from the 3 EBV latency II antigens were generated. These peptides induced IFNγ secretion by PBMCs. Generated peptide-specific CD4+ T cell lines showed highly cytotoxicity against NPC cell lines and resistance to hNPC exosomes. Invivo, the cocktail restrained tumor growth. Exvivo, it reactivated NPC patients’ memory T cells
La, Rochère Philippe de. "La souris humanisée : modèle d'étude de l'immunothérapie anti-cancer A comprehensive analysis of humanized mouse models for the study of cancer immunotherapies Inhibition of PI3K increases immune infiltrate in muscle invasive bladder cancer." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB068.
Повний текст джерелаImmunotherapy is revolutionizing cancer treatment by shifting the treatment strategy from targeting the tumor to targeting the immune system. The blockade of immune checkpoints with anti-CTLA-4, anti-PD1 and anti-PD-L1 antibodies shows impressive clinical results. However, the response rate remains low. It is therefore essential to better understand the mechanisms of action of these therapies, to identify biomarkers of response and toxicity, and to evaluate therapeutic combinations. Such mechanistic and preclinical studies require the optimization of adapted murine models. For these purposes, my PhD work has focused on the development of humanized mouse models, in which immunodeficient mice are grafted with human tumor (cell lines or patient derived xenografts) and immune cells to study different immunotherapy approaches. In humanized mouse models, the human immune cell compartment can be reconstituted from either hematopoietic stem cells (HSC) from umbilical cord blood or with mononuclear cells from human blood (PBMC). We have observed that the injection of HSCs generates several subpopulations of immune cells (myeloid cells, T and B lymphocytes, NK cells), detectable from 4 weeks; while the injection of PBMCs mainly generates T lymphocytes, detectable from 1 week. In the latter model, lymphocyte reconstitution is associated with an anti-tumor effect, but is also accompanied by the development of graft-versus-host disease. Both models have advantages and disadvantages for the evaluation of cancer immunotherapies, which are discussed in my thesis. Using these models, we evaluated the therapeutic effect of a clinically used anti-PD1 antibody on tumor cell lines or on patient derived xenografts of different types of tumors. We observed a heterogeneity in the response to treatment, reflecting the clinical observation of responder and non-responder patients. Finally, in order to evaluate the interest of humanized mice for the study of therapeutic combinations, we tested an anti-PD1 therapy associated with a targeted therapy in bladder cancer. Our results, identifying the strengths and limitations of humanized mice, demonstrate the relevance of these new models for the evaluation of immuno-oncology therapies and open perspectives in the study of therapeutic combinations
Reinhart, Verena [Verfasser], Ernst J. [Akademischer Betreuer] Rummeny, and Vasilis [Akademischer Betreuer] Ntziachristos. "Monitoring of New Immunotherapies for Prostate Cancer with Optical Imaging / Verena Reinhart. Gutachter: Vasilis Ntziachristos ; Ernst J. Rummeny. Betreuer: Ernst J. Rummeny." München : Universitätsbibliothek der TU München, 2013. http://d-nb.info/1047883384/34.
Повний текст джерелаCoulon, Le Moignic Aline. "Développement d'une stratégie de vaccination thérapeutique antitumorale basée sur l'utilisation de lipopolyplexes à ARN ciblant les cellules dendritiques." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066048/document.
Повний текст джерелаElimination of cancer cells requires an efficient cytotoxic immune response. In order to obtain such a response, antigens need to be uptaken by dendritic cells (DCs) and correctly presented to effector cells. We developed a strategy based on RNA lipopolyplexes (LPRs): antigenic mRNA is associated with a histidine-polylysine polyplexe and incorporated in a trimannosylated liposome to better target dendritic cells (DCs) in vivo, as DCs express several C-Type lectin receptors that preferentially bind to mannose. Here, we report that trimannosylated LPRs are efficient to target both human and murine DCs. Interestingly, in vivo experiments reveal that trimannosylated LPRs not only target DCs but also induce their recruitment and activation in draining lymph nodes. Furthermore, when combined with mRNA encoding E7 oncoprotein from HPV16, trimannnosylated LPRs trigger specific T-cell response against E7. Finally, when used as therapeutic vaccines in three different tumors models, LPRs promote curative therapeutic responses in E7-expressing TC1 tumor, in OVA-expressing EG7 lymphoma and in MART-1-expressing B16 melanoma, when combined with E7, OVA or MART-1 mRNA, respectively. Altogether, these results comfort us to considerate the use of this strategy for anti-cancer vaccine therapies
Marabelle, Aurélien. "Targeting Tumor Specific Regulatory T-cells for Cancer Therapy." Thesis, Lyon, École normale supérieure, 2013. http://www.theses.fr/2013ENSL0832.
Повний текст джерелаActivation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, regulatory T-cells (Tregs) eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti–CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response
Mall, Sabine [Verfasser], Angela [Akademischer Betreuer] [Gutachter] Krackhardt, and Iris [Gutachter] Antes. "In vivo monitoring of cancer specific TCR-engineered human T cells by Immuno-PET to analyze pharmacokinetics of T-cell based immunotherapies / Sabine Mall ; Gutachter: Angela Krackhardt, Iris Antes ; Betreuer: Angela Krackhardt." München : Universitätsbibliothek der TU München, 2016. http://d-nb.info/1121206778/34.
Повний текст джерелаSwanson, Anna May. "Novel immunotherapies for EBV-associated cancers." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/2683.
Повний текст джерелаBevers, Robertus Franciscus Maria. "Interactions of BCG with urothelial tumor cells in immunotherapy for superficial bladder cancer." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2004. http://dare.uva.nl/document/74436.
Повний текст джерелаLAGERSIE, PIERRE. "Immunotherapie des tumeurs superficielles de la vessie par le bcg endovesical." Lille 2, 1994. http://www.theses.fr/1994LIL2M332.
Повний текст джерелаGROELL, VALERIE. "Immunotherapie du cancer par transfert adoptif de macrophages actives in vitro." Strasbourg 1, 1990. http://www.theses.fr/1990STR15048.
Повний текст джерелаMARTINEZ, MATHILDE. "Place de l'immunotherapie dans le traitement du cancer du rein metastatique." Toulouse 3, 1993. http://www.theses.fr/1993TOU31506.
Повний текст джерелаGermain, Sylvie. "Essais d'immunotherapie active par fortes doses d'interleukine-2 chez 19 patients porteurs de neoplasies a un stade avance." Lyon 1, 1989. http://www.theses.fr/1989LYO1M234.
Повний текст джерелаHenry, Frédéric. "Immunotherapie des cancers colorectaux : apoptose tumorale et cellules presentatrices d'antigenes (doctorat : biologie des cancers)." Nantes, 1999. http://www.theses.fr/1999NANT20VS.
Повний текст джерелаMoussel, François. "L'interleukine-2 en immunothérapie anticancéreuse." Montpellier 1, 1990. http://www.theses.fr/1990MON11125.
Повний текст джерелаFaivre-Chauvet, Alain. "Optimisation du ciblage diagnostique et therapeutique des tumeurs par trois approches differentes." Nantes, 1994. http://www.theses.fr/1994NANT07VS.
Повний текст джерелаGUILLERAND, MARIE-AUDE. "Dysthyroidies au cours de l'immunotherapie par interleukine 2 en oncologie." Aix-Marseille 2, 1993. http://www.theses.fr/1993AIX20805.
Повний текст джерелаAstoul, Philippe. "Immunotherapie intracavitaire : administration intrapleurale d'interleukine-2 recombinante dans la traitement des cancers pleuraux." Aix-Marseille 2, 1994. http://www.theses.fr/1994AIX22961.
Повний текст джерелаMorgan, Clifford Grant. "Characterization of Tumor Infiltrating Lymphocytes in Pediatric Cancers and the Development of Novel Immunotherapies." Thesis, The George Washington University, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3705722.
Повний текст джерелаCytotoxic T lymphocytes (CTLs) are the primary component of the adaptive immune system responsible for clearance of virally infected and tumorigenic cells. In cancer however, this tumor-specific immune response is often impaired. The impairment is multifactorial; some cancers utilize mechanisms to evade the immune system through downregulation of Major Histocompatability Complex I or lack of tumor-specific antigens, while others use methods to actively inhibit local function of tumor-induced immune responses via production of immunosuppressive cytokines, Fas-mediated apoptosis, or recruitment of T regulatory cells (Tregs). These Tregs function to further immune regulate and inhibit CTLs, using methods such as suppressive cytokines, and cytotoxic killing. All of these components lead to an “on/off” phenotype, where CTL effector function is shut down within the Tumor Immunosuppressive Microenvironment (TIM), but can be recovered quickly upon removal of CTLs from the TIM. The transient impairment of Tumor Infiltrating Lymphocytes (TIL) has been described in mouse models, but is poorly characterized in humans.
In this dissertation, we examined infiltration of CTLs across several types of human pediatric cancers, taken from patients who had not undergone prior treatment. We found tumors associated with favorable prognoses, including Wilms’ Tumor and Neuroblastoma (NB), had higher levels of CTL infiltration than those with less favorable prognoses, e.g. Ependymoma, which possessed no observable infiltration. Additionally, we demonstrate the TIL “on/off” phenotype in a case of Pilocytic Astrocytoma, demonstrating significant recovery of TIL effector function.
We proposed that the poor infiltration and impaired effector function in these pediatric tumors was a direct result of the TIM, and sought to improve this immune response by developing an attenuated live cell vaccine, utilizing a murine NB model, Neuro2a, to create a NB line with knock down (KD) of Inhibitor of Differentiation 2 (Id2), which impaired their ability to form tumors in vivo. In prophylactic and therapeutic models, introduction of Id2-KD cells in combination with the immune checkpoint blockade inhibitor anti-CTLA-4, induced an increase in CTLs capable of homing to the tumor, that were also able to employ effector function within the TIM, resulting in clearance of wild-type Neuro2a tumors.
A separate emerging immunotherapeutic approach is to express a Chimeric Antigen Receptor (CAR) on CTLs that allows them to be activated to kill cells expressing the CAR-specific protein, bypassing MHC presentation. Using a murine Rhabdomyosarcoma model, we demonstrate that tumor infiltrating Tregs express lytic molecules, encouraging us to develop a method of successfully transducing Tregs with a CAR (DC101), rather than CTLs, thereby exploiting characteristics of the Treg in the TIM, specifically their cytotoxic capability and their unique recruitment and ability to thrive in that environment. We demonstrate in vitro CAR-mediated redirection of lytic effector function using DC101-expressing CTLs against tumor cell lines, though attempting to increase Treg cytotoxicity in vitro via known inducers of CTL cytotoxicity (IFNα or IL-12) or known inducers of Tregs within the TIM (TGF-β1) showed no increase in Treg cytotoxicity.
Lequeue, Charlotte. "Expression et fonction de la protéine de costimulation immune BTN3A : identification du ligand de BTN3A2 pour immunothérapie en cancérologie." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0768.
Повний текст джерелаMolecules are presented to Vγ9Vδ2 T cells by immune costimulatory protein BTN3A.BTN3A2 which is devoid of a functional intracellular domain, is overexpressed in 4 cancers. Recently, BTN3A2 was described as regulator of subcellular localization of BTN3A1 thanks to heterodimerization. The aim of our project, was to identify the ligand of BTN3A2 for immunotherapy. Therefore, we have first selected by binding studies using flow cytometry, few T cell lines expressing BTN3A2 ligand.Based on the selection, a gene expression profile comparison was performed and allowed us to establish a list of membrane proteins expressed only in positive cell lines, BTN3A2 ligand candidates. The highest FC were found for HLA class II molecules. Cell lines overexpressing potential candidates of transcriptomic method were used for binding assays using BTN3A2-Fc, but were negative in all conditions. Then cell microarray technology was used to identify potential receptor partners of BTN3A2. 4 remaining gene products were selected, PLPP3, SEMA6A, SEMA6C and MSR1. The validation of these candidates was not done after transient transfection and binding test with BTN3A2-Fc (using flow cytrometry). Moreover, chemoproteomic experiments were performed to isolate and identify by mass spectrometry (MS) BTN3A2 ligand. Therefore, we used an original capture reagent (TFR) with three moieties, allowing covalent binding, which showed clearly BTN3A1 as a potential candidate. In our project, we have confirmed the heterodimerization of BTN3A1/A2 and we have demonstrated an existing form of heterodimerization that could interact with other proteins, to form a signaling pathway activating Vγ9Vδ2 T cells
Duffour, Marie-Thérèse. "Immunisation antitumorale à l'aide d'un vecteur adénoviral codant pour l'antigène de tumeur P815A." Paris 5, 1998. http://www.theses.fr/1998PA05P074.
Повний текст джерелаAUNOBLE, BENEDICTE. "Immunotherapie genique des cancers ovariens : etude des interactions entre p53 et les oncosuppresseurs brca1, brca2 et atm (doctorat : biologie moleculaire)." Clermont-Ferrand 1, 2000. http://www.theses.fr/2000CLF1MM14.
Повний текст джерелаOstankovitch, Marina. "Immunité anti-tumorale et perspectives d'immunothérapie." Paris 5, 1996. http://www.theses.fr/1996PA05P182.
Повний текст джерелаPerrin, Pascale. "Modulation du phenotype de cellules cancereuses coliques chez le rat par le butyrate de sodium : application a l'immunotherapie et a la prevention du cancer du colon (doctorat cancerologie biologique)." Nantes, 1996. http://www.theses.fr/1996NANT10VS.
Повний текст джерелаMerrouche, Yacine. "Application du marquage génique à l'étude du mécanisme d'action de l'immunothérapie cellulaire adoptive dans le carcinome rénal métastatique." Lyon 1, 1997. http://www.theses.fr/1997LYO1T355.
Повний текст джерелаEdes, Inan. "Targeted transduction of T cell subsets for immunotherapy of cancer and infectious disease." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2016. http://dx.doi.org/10.18452/17669.
Повний текст джерелаThe aim of this thesis was to generate a vector system that allows the simultaneous transfer of different transgenes into CD8+ and CD4+ T cells, allowing the generation of a immunotherapeutic T cell product comprised of two differently engineered T cell subsets. The first part of the thesis describes the transfer of the measles virus (MV) envelope-based targeting technology from lentiviral (LV) to γ-retroviral (gRV) vectors. The second part reports the generation of two targeting vectors specific for murine CD4 or CD8. The exclusive specificity of MVm4 and MVm8 was proven by expression of GFP in CD4+ and CD8+ reporter cells, respectively, but not in CD4-CD8- cells after transduction, and by a dose-dependent loss of GFP signal after incubation of reporter cells with CD4 or CD8 blocking antibodies before transduction. The third part shows that MVm8 but not MVm4 transduced primary T cells. MVm8-mediated transfer of the ovalbumin (OVA)-reactive TCR OT-I resulted in T cells secreting interferon-γ (IFNγ) upon recognition of OVA+ tumor cell lines. The final part of this thesis describes the in vivo transduction of primary T cells using MVm8 transferring OT-I and a luciferase (MVm8/OT-I-luc). To this end, B6 mice deficient for Rag2 have been repopulated with either polyclonal (B6) or monoclonal T cells derived from P14-TCR transgenic mice (P14). One day later the transferred T cells were transduced in vivo by systemic application of MVm8/OT-I-luc. Upon immunization in vivo-transduced T cells homed, expanded and contracted repeatedly in an antigen-dependent manner. Finally, mice exhibiting strong luc-signals showed improved protection against infections by OVA-transgenic listeria monocytogenes (LM-OVA). In conclusion, the viral vector system developed within this thesis is able to discriminate between the two main T cell subsets and to equip them with distinct transgenes simultaneously.
Kaiser, Andrew. "Impact de la maturation des cellules dendritiques sur les réponses T spécifiques ou indépendantes de l'antigène : rôle des cytokines et des chimiokines." Paris 6, 2005. http://www.theses.fr/2005PA066058.
Повний текст джерелаSerier, Asma. "Étude de l’activité anti-tumorale des entérotoxines staphylococciques codées par l’enterotoxin gene cluster." Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10171.
Повний текст джерелаThe use of classical superantigens (e.g. SEA, SEB and SEC) for treatment of cancer has resulted in a low response rates due to serious toxicity in humans. However, in a recent clinical study, remarkable results in treating lung cancer were obtained using superantigens encoded by the enterotoxin gene cluster (egc) without causing any significant toxicity. The current study was performed to investigate how egc superantigens (i.e. SEG, SEI, SElM, SElN and SElO) have tumoricidal activity with low toxicity. Indeed, we first demonstrated that tumoricidal activity of egc-SEs is mediated by immune cell activation, in particular, by secretion of soluble mediators such as nitric oxide and TNF-α. Thus, the proteomic analysis of the PBMC supernatants, showed that SEs-egc enhance the expression of pro-inflammatory cytokines, chimokines and many other biomarkers. Interestingly, levels were significantly higher in supernatants of SEA-stimulated PBMC than those with egc superantigens suggesting that staphylococcal superantigens differs in their inflammatory proprerties. Our results suggest that the relative lower pro-inflammatory activity of egc toxins may explain the low toxicity of these toxins observed during the clinical trial. Finally, we showed that SElO have a direct cytostatic activity against tumor cells. These findings suggest that egc-SEs seems to be good candidates for the development of new drugs in cancer therapy
Petitprez, Florent. "Integrated analysis and clinical impact of immune and stromal microenvironments in solid tumors Quantitative analyses of the tumor microenvironment composition and orientation in the era of precision medicine Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies Tumor microenvironment quantification tool draws a comprehensive map of the tumor microenvironment of non-hematologic human cancers The mMCP-counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations using gene expression in murine samples Immune sub-classes in sarcoma predict survival and immunotherapy response Intra-tumoral tertiary lymphoid structures are associated with a low risk of hepatocellular carcinoma early recurrence Association of IL-36γ with tertiary lymphoid structures and inflammatory immune infiltrates in human colorectal cancer Immune-based identification of cancer patients at high risk of progression Tumor-infiltrating and peripheral blood T-cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma PD-L1 expression and CD8+ T-cell infiltrate are associated with clinical progression in patients with node-positive prostate cancer Intratumoral classical complement pathway activation promotes cancer progression". Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB104.
Повний текст джерелаTumors are composed not only of malignant cells but also contain a vast variety of non-malignant cells, notably immune cells forming the tumor microenvironment (TME). The composition of the TME was shown to be associated with clinical outcome for cancer patients, in terms of survival and therapeutic responses. With the relatively recent development of immunotherapies targeting specific elements of the TME, tumor immunology has risen a strong interest and holds a strong therapeutic potential. Several methodologies have been developed to study the composition of the TME with an increased precision. Notably, some methods such as MCP-counter enable the use of the tumor bulk transcriptome to quantify cell populations composing the TME. The methodological aspect of this PhD project consisted in setting up an enhanced version of MCP-counter that can be readily applied to RNA-Seq data, as well as propose an adaptation of the method for mouse models. Using MCP-counter, the TME of large series of tumors can be easily analyzed. The application part of this PhD work consisted of applying MCP-counter to establish an immune-based classification of soft-tissue sarcoma, a rare, aggressive and heterogeneous cancer type. The immune classification notably allowed to identify immune low and high groups, and a group characterized by a strong vasculature. Interestingly, the classification was notably found to be predictive of the patients' response to immunotherapies. It also highlighted an important role of tertiary lymphoid structures (TLS). TLS are lymph-node-like structures composed of T and B cells that form within the tumor or in close proximity. They are a site of formation and maturation of antitumoral immune responses. TLS are raising a growing interest in many malignancies. In most cancer types, a strong infiltration by T cells, in particular CD8+ T cells, is associated with a favorable clinical outcome. However, clear-cell renal cell carcinoma and prostate cancer are exceptions to this general rule. Indeed, in these urological cancers, an increased infiltration by T cells is associated with a decreased patient survival and with earlier relapse and disease progression. In a third part of this thesis, these exceptions are investigated with more details by scrutinizing the TME, and questioning the implication of the complement system. Overall, this thesis presents how the combination of several analysis methods, in silico, in situ and in vivo, can help achieve an extremely precise description of the TME. Knowing accurately what cell populations and what their functional orientation can help guide patients care and improve clinical outcome. Complete description of the TME opens the way towards personalized medicine for cancer patients
Servais, Charlotte. "Mise au point de thérapies anti-tumorales impliquant des vecteurs parvoviraux et la fusion de cellules tumorales et dendritiques." Doctoral thesis, Universite Libre de Bruxelles, 2007. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210624.
Повний текст джерелаL’intérêt majeur du parvovirus autonome MVM en tant que vecteur pour la thérapie génique du cancer vient de son expression préférentielle dans les cellules transformées (oncotropisme) et de son aptitude à lyser celles-ci (oncolyse). Les vecteurs générés au laboratoire conservent l’unité de transcription NS et expriment l’IL2 humaine sous contrôle du promoteur P38, à la place des protéines de capside. Malgré les améliorations apportées à la production de vecteurs recombinants, la faible concentration des stocks reste un problème. Il a été montré que, de nombreux virus sont mieux produits en conditions de faible tension en oxygène (hypoxie). Nous avons tenté d’améliorer les titres des vecteurs en les produisant sous faible tension d’oxygène mais sans y parvenir (annexe 1). Dans un modèle in vivo utilisant la lignée de mélanome K-1735 dans des souris immunocompétentes, des cellules tumorales infectées in vitro avant leur implantation en sous-cutané ont montré un effet anti-tumoral du vecteur MVM/IL2 (annexe 2). Afin de mettre en évidence l’apport de l’oncolyse parvovirale dans l’activité anti-tumorale, nous avons mis au point des expériences, dans le même modèle de tumeur, visant à comparer l’efficacité du vecteur MVM/IL2 à celle d’autres vecteurs, Ad/IL2 et Rétrovirus/IL2, ne possédant pas d’activité oncolytique. Dans le but de mettre en évidence une éventuelle réponse immune in vivo, nous avons utilisé le modèle de tumeur TC-1 mais ce modèle s’est montré moins sensible à l’effet du vecteur MVM/IL2 et nous n’avons pas pu démontrer d’activation de cellules cytotoxiques spécifiques de la tumeur.
Il a été proposé d’utiliser des hybrides entre DC/TC pour la vaccination anti-tumorale pour optimaliser la présentation des antigènes tumoraux. Une lignée cellulaire exprimant la protéine fusogène du virus de la leucémie du Gibbon (GaLV-FMG, Gibbon ape leukemia virus) a été dérivée de la lignée cellulaire CHO (cellules ovariennes de hamster chinois) au laboratoire. Cette lignée CHO-FMG, utilisée comme partenaire intermédiaire, a permis la fusion entre cellules tumorales et dendritiques (annexe 3). Nous avons montré que l’expression transitoire après infection par un vecteur AAV-FMG ou après transfection transitoire ne génère pas un pourcentage significatif d’hybrides. En effet, le niveau d’expression ainsi que le pourcentage de cellules transduites exprimant FMG s’est révélé trop faible. Ceci a mis en valeur l’efficacité de la lignée stable CHO-FMG comme intermédiaire de la fusion. De plus, nous avons intégré dans la lignée fusogène, le gène de l’interleukine-2, qui devrait permettre d’augmenter l’efficacité de l’induction de la réponse immune.
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Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished
Ravaud, Alain. "Modèle in vitro d'immunisation active antitumorale humaine par des cellules de présentation." Bordeaux 2, 1998. http://www.theses.fr/1998BOR28579.
Повний текст джерелаDuperrier, Karine. "Génération, caractérisation et immunomodulation des cellules dendritiques issues de monocytes humains." Lyon 1, 2000. http://www.theses.fr/2000LYO1T221.
Повний текст джерела"Mathematical Modeling of Novel Cancer Immunotherapies." Doctoral diss., 2020. http://hdl.handle.net/2286/R.I.62684.
Повний текст джерелаDissertation/Thesis
Doctoral Dissertation Applied Mathematics 2020
Loios, Rita Severino dos. "Optimization of strategies for anti-cancer vaccines." Master's thesis, 2018. http://hdl.handle.net/10362/65527.
Повний текст джерела"Developing a CRISPR-Mediated Knockout TCR Human T Cell Line for Use in Cloning Antigen-Specific T Cell Receptors." Master's thesis, 2020. http://hdl.handle.net/2286/R.I.57440.
Повний текст джерелаDissertation/Thesis
Masters Thesis Biology 2020