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1
Tartour, E., R. S. Lee, and W. H. Fridman. "Anti-cytokines: promising tools for diagnosis and immunotherapy." Biomedicine & Pharmacotherapy 48, no. 10 (January 1994): 417–24. http://dx.doi.org/10.1016/0753-3322(94)90002-7.
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van Montfrans, C., L. Camoglio, and S. J. H. van Deventer. "Immunotherapy of Crohn's disease." Mediators of Inflammation 7, no. 3 (1998): 149–52. http://dx.doi.org/10.1080/09629359891063.
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Although the initiating events of Crohn's disease are unknown, models of experimental colitis have provided new insights in the immunologically mediated pathways of mucosal inflammation. In Crohn's disease activated mucosal T lymphocytes produce proinflammatory cytokines within the mucosal compartment. With this understanding, there has been a shift in past years from the use of unspecific anti-inflammatory agents (corticosteroids, aminosalicylates) to the use of immunomodulatory drugs (azathioprine, methotrexate). Moreover, novel strategies have been designed for specific targets in Crohn's disease, in particular T lymphocytes and cytokines. In an open label study treatment of steroid-refractory Crohn's disease with anti- CD4+ antibodies was well tolerated and showed clinical benefit. However, a sustained depletion of the CD4+ cells precluded further clinical trials. In controlled clinical studies, anti-tumour necrosis factor (TNF-α) antibodies induced com plete remissions and few side effects were observed. One study suggested efficacy in active Crohn's disease of recombinant interleukin-10. Long term treatment studies will have to answer questions about the indications for use, benefit and toxicity. Altogether, these results hold promise for future management of Crohn's disease, where disease-modifying interventions and strategies that effectively maintain disease remission will play a key role.
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Bhushan, Monica, Nicholas M. Craven, and Christopher E. M. Griffiths. "Immunotherapy of Psoriasis." Journal of Cutaneous Medicine and Surgery 1, no. 3 (January 1997): 175–84. http://dx.doi.org/10.1177/120347549700100313.
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Background: Psoriasis is a common inflammatory skin disease, characterized by epidermal keratinocyte hyperproliferation and an inflammatory infiltrate. Current research indicates that epidermal hyperproliferation is, in part, dependent upon the milieu of cytokines and growth factors produced chiefly by T cells within the infiltrate and that the T cells play a central role in the pathogenesis of psoriasis. Objective: Recent developments in the treatment of psoriasis are discussed in the context of current understanding of the pathogenesis of this condition. Conclusion: Significant advances are being made in the treatment directed against these specific immunologic aberrations. Efficacy of immunosuppressive agents such as cyclosporine, FK506 (tacrolimus), anti-CD4 monoclonal antibodies, and IL-2 fusion-toxin in the treatment of psoriasis underscore its probable immune basis. Highly specific treatment directed against cytokines, angiogenesis, and adhesion molecules remains experimental, but shows promise for safer systemic treatment in the future.
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Lee, J. H., S. Y. Lim, A. M. Menzies, M. S. Carlino, A. Guminski, K. Nahar, D. Palmieri, et al. "Pre-treatment circulating cytokines predict toxicity with combination anti-PD1 and anti-CTLA4 immunotherapy." Annals of Oncology 29 (October 2018): viii659. http://dx.doi.org/10.1093/annonc/mdy303.031.
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Gordon, Bruce R. "Future Immunotherapy: What Lies Ahead?" Otolaryngology–Head and Neck Surgery 113, no. 5 (November 1995): 603–5. http://dx.doi.org/10.1177/019459989511300512.
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There is currently great interest in developing improved methods of immunotherapy and new techniques of immune system manipulation to ameliorate allergic diseases. This article reviews current research trends in the immunologic treatment of allergy, including the use of chemically modified allergens, nonparenteral allergen exposure, sustained-release allergen delivery, anti-immunoglobulin E antibodies, γ-globulin, immune complexes, cytokines, and T-cell-tolerogenic peptides.
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Bacot, Silvia M., Taylor A. Harper, Rebecca L. Matthews, Christie Jane Fennell, Adovi Akue, Mark A. KuKuruga, Shiowjen Lee, Tao Wang, and Gerald M. Feldman. "Exploring the Potential Use of a PBMC-Based Functional Assay to Identify Predictive Biomarkers for Anti-PD-1 Immunotherapy." International Journal of Molecular Sciences 21, no. 23 (November 27, 2020): 9023. http://dx.doi.org/10.3390/ijms21239023.
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The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell functions, the primary mechanism of action of anti-PD-1 therapy. In this study, we established a model system to test T cell functions modulated by Nivolumab using anti-CD3 monoclonal antibody (mAb)-stimulated peripheral blood mononuclear cells (PBMCs), and characterized T cell functions primarily based on the knowledge gained from retrospective observations of patients treated with anti-PD-1 immunotherapy. During a comprehensive cytokine profile assessment to identify potential biomarkers, we found that Nivolumab increases expression of T helper type 1 (Th1) associated cytokines such as interferon-γ (IFN-γ) and interleukin-2 (IL-2) in a subset of donors. Furthermore, Nivolumab increases production of Th2, Th9, and Th17 associated cytokines, as well as many proinflammatory cytokines such as IL-6 in a subset of donors. Conversely, Nivolumab treatment has no impact on T cell proliferation, expression of CD25, CD69, or Granzyme B, and only modestly increases in the expansion of regulatory T cells. Our results suggest that assessment of cytokine production using a simple PBMC-based T cell functional assay could be used as a potential predictive marker for anti-PD-1 immunotherapy.
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Terlikowska, K. M., B. Dobrzycka, and SJ Terlikowski. "Ovarian cancer and inflammation. Part 2. Anti-inflammatory cytokines." Progress in Health Sciences 8, no. 2 (December 31, 2018): 206–9. http://dx.doi.org/10.5604/01.3001.0012.8348.
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Inflammation plays a key role in epithelial ovarian cancer tumorigenesis and progression. The growth and progression of epithelial ovarian cancer may be due to local cytokine-induced immunosu-ppression, which may lead to an immunity impairment. Thus, cytokine antagonism may be an essential factor in the treatment of ovarian cancer. Based on the increased knowledge on the role of the immune system in ovarian cancer, major improvements are to be expected of immunotherapy based treatment of this disease. This article aims to summarize the current literature views on the evidence for a role for chronic inflammation with a specific focus on anti-inflammatory cytokines.
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Dimitrov, Dimitre H., Shuko Lee, Jesse Yantis, Craig Honaker, and Nicole Braida. "Cytokine Serum Levels as Potential Biological Markers for the Psychopathology in Schizophrenia." Advances in Psychiatry 2014 (December 11, 2014): 1–7. http://dx.doi.org/10.1155/2014/493505.
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We discuss the role of immune system disturbance in schizophrenia and especially changes of serum levels of cytokines in patients with schizophrenia. The cytokines are essential to wide range of functions related to the defense of the organisms from infectious and environmental dangers. However it is not known whether cytokines influence the presentation of psychotic symptoms. Identification of changes in the serum level of certain cytokines and their correlation with distinct psychopathological symptoms may facilitate the identification of subgroups of patients who are likely to benefit from immunotherapy or anti-inflammatory therapy. Such patients may benefit from tailored immunotherapy designed for modulation of abnormal cytokine levels related to specific positive or negative symptoms of schizophrenia.
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Mirlekar, Bhalchandra, and Yuliya Pylayeva-Gupta. "IL-12 Family Cytokines in Cancer and Immunotherapy." Cancers 13, no. 2 (January 6, 2021): 167. http://dx.doi.org/10.3390/cancers13020167.
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The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.
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Chung, Fan. "Anti-inflammatory cytokines in asthma and allergy: interleukin-10, interleukin-12, interferon-γ." Mediators of Inflammation 10, no. 2 (2001): 51–59. http://dx.doi.org/10.1080/09629350120054518.
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Interleukin-10 (IL-10) is a cytokine derived fromCD4+T-helper type 2 (TH2) cells identified as a suppressor of cytokines from T-helper type 1(TH1) cells. Interleukin-12 (IL-12) is produced by B cells, macrophages and dendritic cells, and primarily regulates TH1cell differentiation, while suppressing the expansion of TH2cell clones. Interferon-γ (IFN-γ) is a product of TH1cells and exerts inhibitory effects on TH2cell differentiation. These cytokines have been implicated in the pathogenesis of asthma and allergies. In this context, IL-12 and IFN-γ production in asthma have been found to be decreased, and this may reduce their capacity to inhibit IgE synthesis and allergic inflammation. IL-10 is a potent inhibitor of monocyte/macrophage function, suppressing the production of many pro-inflammatory cytokines. A relative underproduction of IL-10 from alveolar macrophages of atopic asthmatics has been reported. Therapeutic modulation of TH1/TH2imbalance in asthma and allergy by mycobacterial vaccine, specific immunotherapy and cytoline-guanosine dinucleotide motif may lead to increases in IL-12 and IFN-γ production. Stimulation of IL-10 production by antigen-specific T-cells during immunotherapy may lead to anergy through inhibition of CD28-costimulatory molecule signalling by IL-10s anti-inflammatory effect on basophils, mast cells and eosinophils.
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Frati, F., S. Scurati, P. Puccinelli, C. Morviducci, G. Di Cara, R. Boccardo, E. Piergentili, et al. "Inflammation in Respiratory Allergy Treated by Sublingual Immunotherapy." European Journal of Inflammation 7, no. 3 (September 2009): 121–29. http://dx.doi.org/10.1177/1721727x0900700301.
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The most common allergic diseases, such as rhinitis, asthma and atopic dermatitis, are sustained by allergic inflammation, the treatment of which requires anti-inflammatory activity. Among the available treatments, allergen immunotherapy (IT) has a documented impact on allergic inflammation which persists after its discontinuation and modifies the natural course of allergy. The anti-inflammatory effects of IT, and particularly of sublingual IT (SLIT), are based on the ability to modify the phenotype of T cells which, in allergic subjects, are characterized by a prevalence of the Th2 type, with production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines. IT-induced changes result in a Th1-type response (immune deviation) related to an increased IFN-gamma and IL-2 production or in a Th2 reduced activity, through a mechanism of anergy or tolerance. It is now known that T cell tolerance is characterized by the generation of allergen-specific Treg cells, which produce cytokines such as IL-10 and TGF-beta with immunosuppressant and/or immunoregulatory activity. Recent studies suggest that the anti-inflammatory mechanism of SLIT is similar to classical, subcutaneous IT, with a prominent role in SLIT for mucosal dendritic cells. The tolerance pattern induced by Treg accounts for the suppressed or reduced activity of inflammatory cells and for the isotypic switch of antibody synthesis from IgE to IgG, and especially to IgG4. Data obtained from biopsies clearly indicate that the pathophysiology of the oral mucosa plays a pivotal role in inducing tolerance to the sublingually administered allergen.
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Kim, Esther, Hyeok Ahn, and Hansoo Park. "A review on the role of gut microbiota in immune checkpoint blockade therapy for cancer." Mammalian Genome 32, no. 4 (March 30, 2021): 223–31. http://dx.doi.org/10.1007/s00335-021-09867-3.
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AbstractGut microbiota has been studied in relation to human health and disease prediction for decades. Also, immune checkpoints (ICPs) are enthusiastically investigated for anti-tumor immunotherapy. Recent studies show potential of gut microbiome and gut cytokines as biomarkers for carcinogenesis and response prediction of immune checkpoint inhibitor (ICI) response. Evidence has revealed that intestinal microorganisms play a major role in the effectiveness of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade. In this review, we have focused on how microbiome and microbiome-generated cytokines affect immune checkpoints. We have also described the molecular mechanisms behind this interplay and the bacterial strains that have a potential role in immunotherapy.
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Pawelec, Graham P. "Immunosenescence and cancer immunotherapy." Journal of Clinical Oncology 35, no. 7_suppl (March 1, 2017): 42. http://dx.doi.org/10.1200/jco.2017.35.7_suppl.42.
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42 Background: Geriatric oncology, important for the ever-increasing numbers of elderly cancer patients, has thus far focused primarily on tolerance to chemotherapy. With the advent of breakthrough immunomodulatory antibody treatments relying on the patient´s own immune system to control the tumor, the issue of immunosenescence becomes extremely important. There is increasingly a valid concern that anti-cancer immunity may be compromised in the elderly due to i) their low amounts of naïve T-cells (leading to holes in the repertoire for neoantigens) and ii) “exhaustion” of potentially tumor-specific memory T-cells. Encouragingly, but only anecdotally, accumulated clinical experience (thus far, limited to melanoma treated with anti-CTLA-4 antibodies) suggests that advanced aged does not result in decreased responses or increased side effects. However, the fraction of patients experiencing clinical benefit was low, and broader and more detailed studies focusing on the age question are required. Methods: In our own work, we have established prognostic phenotypic and functional “immune signatures” using peripheral blood from younger melanoma and breast cancer patients, which comprise phenotypic T-cell and myeloid-derived suppressor cell quantification and measurement of pro- and anti-inflammatory CD4+ and CD8+ T-cell responses to shared tumor antigens such as NY-ESO-1 and Her2 in vitro using intracytoplasmic flow cytometry to detect 6 cytokines simultaneously. Results: We found that these peripheral immune signatures were equally prognostic in older patients ( > 80 years of age). Conclusions: We therefore conclude that immunosenescence should not be a barrier to anti-tumor immunity in elderly people treated with immunomodulatory antibodies, at least for responses targeting shared tumor antigens. It remains to be established whether responses to tumor neoantigens are compromised by immunosenescence. Given the current emphasis on neoantigen responsiveness, this remains a concern.
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Chiovaro, Francesca, Silvan Strebel, Armin Wolf, Wolfgang Moritz, and Irina Agarkova. "Screening immunotherapy cancer drugs in a scalable, physiologically relevant 3D in vitro tumor microenvironment model." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 12.07. http://dx.doi.org/10.4049/jimmunol.206.supp.12.07.
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Abstract Interaction of tumor cells with surrounding stromal and immune cells, secreted cytokines, and extracellular matrix proteins, collectively known as the tumor microenvironment (TME), is crucial for cancer progression and metastasis. Here, we present a novel 3D in vitro TME model to assess candidate drugs for cancer therapy. For this study, we prepared lung carcinoma spheroids from GFP-A549 cells co-cultured with cancer-associated fibroblasts (CAFs) and PBMCs. To simulate a pro-inflammatory tumor microenvironment, we activated PBMCs with cytokines and/or anti-CD3/CD28. We assessed the effect of PD-1 inhibitors in combination with cytokines for potential synergistic anti-cancer effects. We then developed a tumor model using melanoma PDX cells labeled with CellTracker to monitor tumor cell viability after exposure to activated PBMCs. We evaluated killing activity and effector function of T cells by measuring tumor microtissue size by automatic stage fluorescence microscopy and release of IL-6, TNFa, IFNγ and GM-CSF with a MAGPIXTM Luminex system over time. Immune cell infiltration and its effects on tumor were assessed by histological analysis using tumor, immune cell and apoptosis markers. Our results show combination treatment with cytokines and anti-PD-1 antibody led to higher secretion of IL-6/TNFa/IFNγ/GM-CSF, reduced tumor size, increased infiltration of the model by CD8+ T cells, stronger expression of Granzyme B resulting in enhanced tumor apoptosis and killing. This confirms our novel 3D in vitro TME model is a promising tool for studying cell-cell interactions and allows for HCS of novel candidates for anti-cancer drugs.
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Müller, Ludmila, and Graham Pawelec. "Cytokines and Antitumor Immunity." Technology in Cancer Research & Treatment 2, no. 3 (June 2003): 183–94. http://dx.doi.org/10.1177/153303460300200302.
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Currently, the notion of immunosurveillance against tumors is enjoying something of a renaissance. Even if we still refuse to accept that tumors arising in the normal host are unable to trigger an immune response because of the lack of initiation (“danger”) signals, there is no doubt that the immune system can be manipulated experimentally and by implication therapeutically to exert anti-tumor effects. For this activity to be successful, the appropriate cytokine milieu has to be provided, making cytokine manipulation central to immunotherapy. On the other hand, the major hurdle currently preventing successful immunotherapy is the ability of tumors to evolve resistant variants under the pressure of immune selection. Here, too, the cytokine milieu plays an essential role. The purpose of this brief review is to consider the current status of the application of cytokines in facilitating antitumor immunity, as well their role in inhibiting responses to tumors. Clearly, encouraging the former but preventing the latter will be the key to the effective clinical application of cancer immunotherapy.
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Khatibi, Azadeh Sharif, Nasim Hayati Roodbari, Keivan Majidzade-A, Parichehreh Yaghmaei, and Leila Farahmand. "In vivo tumor-suppressing and anti-angiogenic activities of a recombinant anti-CD3ε nanobody in breast cancer mice model." Immunotherapy 11, no. 18 (December 2019): 1555–67. http://dx.doi.org/10.2217/imt-2019-0068.
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Aim: Achievements in cancer immunotherapy require augmentation of a host's anti-tumor immune response for anti-cancer modality. Materials & methods: Different concentrations of recombinant anti-CD3 nanobody were administered at predetermined time intervals during a 24-day treatment period and then expression of angiogenic biomarkers including VEGFR2, MMP9 and CD31, as well as tumor cell proliferation marker ki67, was determined in tumor sections by immunohistochemistry. Furthermore, expression of cytokines was examined in peripheral blood of mice. Results: Based on our results, administration of nanobody could reduce biomarker expression in tumor sections. Tumor growth was also delayed and survival rate was increased in response to nanobody treatment. Moreover, expression of pro-inflammatory cytokines was reduced. Conclusion: In conclusion, we demonstrated that administration of nanobody could effectively suppress angiogenesis as well as tumor growth.
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Tung, Chun-Yu, Sharifah Kyazike, David Lewis, Ling Han, Alexander Kolb, David Pelloso, Anthony Sinn, et al. "Activation Of Natural Killer Cells By Soypeptide Lunasin and Cytokine: Implication In Cancer Immunotherapy For Lymphoma." Blood 122, no. 21 (November 15, 2013): 1042. http://dx.doi.org/10.1182/blood.v122.21.1042.1042.
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Abstract Introduction Immunostimulatory cytokines can enhance anti-tumor immunity and are part of the therapeutic armamentarium for cancer treatment. We have previously reported that chemotherapy-treated lymphoma patients have acquired deficiency of Signal Transducer and Activator of Transcription 4 (STAT4), which results in defective IFNg production during clinical immunotherapy. With the goal of further improvement in cytokine-based immunotherapy, we examined the effects of a soybean peptide called lunasin that exhibits immunostimulatory effects on natural killer (NK) cells. Experimental Design PBMCs of healthy donors and chemotherapy-treated lymphoma patients were stimulated with or without lunasin in the presence of IL-12 or IL-2. NK activation was evaluated, and its tumoricidal activity was assessed using in vitro and in vivo tumor models. Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the histone modification of gene loci that are regulated by lunasin and cytokine. Results Adding lunasin to IL-12- or IL-2-cultuted NK cells demonstrated synergistic effects in the induction of IFNG and genes involved in cytotoxicity. The expression level of CD16 and granzyme B was increased in CD56-bright population of NK cells following stimulation with lunasin and cytokine. The combination of lunasin and cytokines (IL-12 plus IL-2) was capable of restoring IFNg production by NK cells from post-transplant lymphoma patients. In addition, NK cells stimulated with lunasin plus cytokines had higher tumoricidal activity than those stimulated with cytokines alone using in vitro and in vivo tumor models. Moreover, lunasin augmented antibody-dependent cellular cytotoxicity (ADCC) of NK cells against anti-CD20 coated human B-lymphoma cell line. The underlying mechanism responsible for the effects of lunasin on NK cells is likely due to epigenetic modulation on target gene loci. Conclusion We have discovered a novel use of lunasin that exerts synergistic effects together with IL-12 or IL-2. This synergism leads to stronger NK-mediated anti-tumor activity, suggesting the potential clinical use of lunasin to augment the therapeutic responses in cytokine-based immunotherapy. Disclosures: No relevant conflicts of interest to declare.
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Redmond, William, Stefanie Linch, and Melissa Kasiewicz. "Combination of agonist anti-OX40 therapy with CTLA-4 blockade augments anti-tumor effector CD4 and CD8 T cells (P4318)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 45.7. http://dx.doi.org/10.4049/jimmunol.190.supp.45.7.
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Abstract Ligation of the TNF receptor family co-stimulatory molecule OX40 (CD134) with an agonist anti-OX40 mAb enhances anti-tumor immunity by augmenting CD4 and CD8 T cell clonal expansion, effector differentiation, as well as turning off the suppressive activity of FoxP3+CD4+ regulatory T cells (Treg). Moreover, the targeted blockade of the checkpoint inhibitor CTLA-4 on CD4 effector and Treg cells enhances anti-tumor immunity by boosting effector T cell responses and alleviating the suppressive capacity of Treg. However, monotherapy with anti-OX40 or anti-CTLA-4 mAb can have limited efficacy, particularly against poorly immunogenic tumors. Therefore, we investigated whether combination immunotherapy could overcome this defect to generate optimal therapeutic responses. We demonstrate that combined anti-OX40/anti-CTLA-4 therapy significantly enhanced tumor regression and survival of TRAMP-C1 prostate or MCA-205 sarcoma tumor-bearing hosts. Mechanistic studies revealed that combined anti-OX40/anti-CTLA-4 therapy elicited CD8 T cell proliferation and differentiation as well as the expansion of effector CD4 T cells producing Th1 and Th2 cytokines, but did not inhibit the expansion or suppressive function of Treg cells. Together, these data demonstrate that combined anti-OX40/anti-CTLA-4 immunotherapy elicits potent anti-tumor immunity and indicate that clinical evaluation of this combination regimen to boost tumor immunotherapy is warranted.
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Антонюк, Марина, Marina Antonyuk, С. Сулейманов, S. Suleymanov, Татьяна Гвозденко, Tatyana Gvozdenko, Татьяна Новгородцева, and Tatyana Novgorodtseva. "EFFICIANCY OF IMMUNOTHERAPY IN PATIENTS WITH PERSISTENT ALLERGIC RHINITIS." Bulletin physiology and pathology of respiration 1, no. 70 (December 29, 2018): 32–37. http://dx.doi.org/10.12737/article_5c1264ee93f132.73406573.
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The dynamics of parameters of cytokine status in patients with allergic rhinitis in view of efficiency of allergen-specific immunotherapy (ASIT) was studied in this work. 62 subjects with moderate persistent rhinitis at the age of 18-40 years old were included in the study. For specific diagnosis and treatment there we used standard allergens. ASIT was performed by the classical scheme. The concentrations of IL-4, IL-5, IL-6, IL-8 in the blood serum were measured by the enzyme immunoassay. A good or excellent effect of treatment with ASIT was achieved in 62.9% of cases, and satisfactory one in 37.1% of cases. The analysis of the dynamics of IL-4, IL-5, IL-6, IL-8 concentrations showed that the efficiency of ASIT in patients with allergic rhinitis depends on the ability of the immune system to activation by low doses of the allergen, quite fast suppression of proinflammatory cytokines induced by them, and active functioning of the system of anti-inflammatory cytokines.
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Luo, Kewang, Ning Li, Wei Ye, Hanchao Gao, Xinle Luo, and Baohui Cheng. "Activation of Stimulation of Interferon Genes (STING) Signal and Cancer Immunotherapy." Molecules 27, no. 14 (July 20, 2022): 4638. http://dx.doi.org/10.3390/molecules27144638.
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Stimulator of interferon gene (STING), an intracellular receptor in the endoplasmic reticulum, could induce the production of cytokines such as type I interferon (IFN) by activating the cGAS-STING signal pathway. In recent years, activation of STING has shown great potential to enhance anti-tumor immunity and reshape the tumor microenvironment, which is expected to be used in tumor immunotherapy. A number of STING agonists have demonstrated promising biological activity and showed excellent synergistic anti-tumor effects in combination with other cancer therapies in preclinical studies and some clinical trials. The combination of STING agonists and ICI also showed a potent effect in improving anti-tumor immunity. In this review, we introduce the cGAS-STING signaling pathway and its effect in tumor immunity and discuss the recent strategies of activation of the STING signaling pathway and its research progress in tumor immunotherapy.
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Shute, Travis J., Elizabeth Dudley, Joshua Naranjo, Wendell Griffith, Kelly Nash, and Elizabeth Leadbetter. "Glycolipid-loaded Nanoparticles Harness iNKT cells for Tumor Immunotherapy." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 29.12. http://dx.doi.org/10.4049/jimmunol.206.supp.29.12.
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Abstract Invariant natural killer T cells (iNKT) have a well-documented role in anti-tumor immunity through their release of proinflammatory cytokines and cytotoxic compounds. As iNKT cells can have direct and indirect killing effects on tumor cells, we propose a novel strategy for activating iNKT cells, via a PLGA nanoparticle delivery platform, to promote anti-tumor immune responses. Poly-lactic-co-glycolic acid (PLGA) nanoparticles can be reproducibly loaded with an iNKT cell glycolipid agonist, alpha-galactosylceramide (alpha-GalCer), and a model tumor associated antigen, ovalbumin (OVA). These dual-loaded PLGA nanoparticles rapidly activate iNKT cells in vivo to produce IFNgamma. Furthermore, in an in vivo model of melanoma, using B16F10-OVA cells, both prophylactic and therapeutic administration of nanoparticles containing alpha-GalCer and OVA led to decreased tumor cell growth and increased survival. We also show our nanoparticle therapy has synergistic potential with two immune checkpoint blockade therapies, anti-PD-1 and anti-CTLA-4, currently used in the clinic for human cancer patients. This novel delivery system provides a platform with tremendous potential to harness iNKT cells for cancer immunotherapy purposes against many different cancer types.
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Yap, Wei Boon, Shaktypreya Nadarajah, Nadiah Shidik, and Noorjahan Banu Mohammed Alitheen. "Potentials of interleukin-27 (IL-27) as an immunotherapeutic cytokine in cancer therapy." Trends in Immunotherapy 3, no. 2 (August 15, 2019): 76. http://dx.doi.org/10.24294/ti.v3.i2.121.
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Cancer immunotherapy using cytokines has been sought as an alternative therapeutic approach for treating cancers. Besides remarkable immunoregulatory properties, interleukin (IL)-27 has recently been shown to possess promising anticancer functions; hence, its potential roles in cancer immunotherapy. Although proven to be effective against cancer cell growth and angiogenesis, given its dual immune-regulating functions (pro-inflammatory and anti-inflammatory), the use of IL-27 as a cancer immunotherapeutic cytokine could possibly be a two-edged sword without meticulous and thorough research. This mini-review mainly discusses the functions and future prospects of IL-27 as an effective anticancer cytokine. Hopefully, it imparts useful insights into the potential applications of IL-27 in cancer immunotherapy
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Guo, Libin, Yao Lin, and Hang Fai Kwok. "The function and regulation of PD-L1 in immunotherapy." ADMET and DMPK 5, no. 3 (September 29, 2017): 159. http://dx.doi.org/10.5599/admet.5.3.442.
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PD-L1, also known as B7-H1, is a type I transmembrane protein, which is expressed in different kinds of tumor cells. It is correlated with poor clinical outcome of patients with various types of tumors. PD-L1 can regulate tumor microenvironment or tumor related immune response through suppressing T cell or NK cell mediated immune response. PD-L1 expression is regulated by various cytokines, such as LPS, GM-CSF, IL-4, TGF-β, TNF-α. PD-1 and PD-L1 are the members of B7 and CD28 superfamily, respectively. The B7/CD28 interaction plays a central role in immune tolerance. PD-L1 can bind to PD-1, which leads to the suppression of lymphocyte activation and apoptosis of lymphocytes. Anti-PD-L1 therapy is one of the immunotherapies to treat cancer (especially solid tumor). PD-L1 expression may be associated with efficacy of anti PD-1/PD-L1 therapy. In this review, we will focus on the regulation mechanism of PD-L1 expression, and describe the role of PD-1/PD-L1 binding on the anti-PD-1/PD-L1 therapy.
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Sordo-Bahamonde, Christian, Massimo Vitale, Seila Lorenzo-Herrero, Alejandro López-Soto, and Segundo Gonzalez. "Mechanisms of Resistance to NK Cell Immunotherapy." Cancers 12, no. 4 (April 7, 2020): 893. http://dx.doi.org/10.3390/cancers12040893.
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Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK cells include monoclonal antibodies that promote NK cell antibody-dependent cell-mediated cytotoxicity (ADCC), hematopoietic stem cell transplantation (HSCT), the adoptive transfer of NK cells, the redirection of NK cells using chimeric antigen receptor (CAR)-NK cells and the use of cytokines and immunostimulatory drugs to boost the anti-tumor activity of NK cells. Despite some encouraging clinical results, patients receiving these therapies frequently develop resistance, and a myriad of mechanisms of resistance affecting both the immune system and cancer cells have been reported. A first contributing factor that modulates the efficacy of the NK cell therapy is the genetic profile of the individual, which regulates all aspects of NK cell biology. Additionally, the resistance of cancer cells to apoptosis and the immunoediting of cancer cells, a process that decreases their immunogenicity and promotes immunosuppression, are major determinants of the resistance to NK cell therapy. Consequently, the efficacy of NK cell anti-tumor therapy is specific to each patient and disease. The elucidation of such immunosubversive mechanisms is crucial to developing new procedures and therapeutic strategies to fully harness the anti-tumor potential of NK cells.
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Cavanagh, Jonathan, and Christopher Mathias. "Inflammation and its relevance to psychiatry." Advances in Psychiatric Treatment 14, no. 4 (July 2008): 248–55. http://dx.doi.org/10.1192/apt.bp.106.003319.
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Depression is increasingly recognised as a major public health problem worldwide. The heterogeneity of this condition implies that there may be several neurobiological pathways to depression. This article attempts to explore a pathway that links depression with the inflammatory response. Associations linking inflammation and chronic immune activation with depression have been noted, particularly in the context of (a) medical disorders with inflammatory pathophysiology and (b) immunotherapy for cancer and hepatitis C. Acute coronary syndrome is given as an example of how the inflammatory process might result in depression, and potential mechanisms are discussed. These include: direct action of pro-inflammatory cytokines on the serotonin system, with specific reference to the serotonin transporter; action of cytokines on the hypothalamic–pituitary–adrenal axis; and effects of pro-inflammatory cytokines on neurogenesis in the hippocampus. Reference is made to the potential anti-inflammatory effects of antidepressant drugs and antidepressant effects of anti-inflammatory treatments.
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Lim, Su Y., Jenny H. Lee, Tuba N. Gide, Alexander M. Menzies, Alexander Guminski, Matteo S. Carlino, Edmond J. Breen, et al. "Circulating Cytokines Predict Immune-Related Toxicity in Melanoma Patients Receiving Anti-PD-1–Based Immunotherapy." Clinical Cancer Research 25, no. 5 (November 8, 2018): 1557–63. http://dx.doi.org/10.1158/1078-0432.ccr-18-2795.
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Carrilho, Allana Bandeira, Patricia Bandeira Carrilho, and Luiz Arthur Calheiros Leite. "Mechanisms and effectiveness of immunotherapy in patients infected with COVID-19." Revista Eletrônica Acervo Saúde 13, no. 2 (February 24, 2021): e5632. http://dx.doi.org/10.25248/reas.e5632.2021.
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Objective: To investigate the mechanism and effectiveness of immunotherapy in patients infected with COVID-19. Literature review: Inflammation for cytokines are directly associated with the development of COVID-19 and its severity, due to the cytokine storm, immunological pulmonary injury and systemic damage. When infected, the patient develops an inflammatory chain that results in a large quantity of pro-inflammatory cytokines, the cytokine storm, leading to fast development of the disease. The status of hyperinflammation and inflammatory biomarkers are essential tools to this disease prognosis. These biomarkers, complete blood count, CRP, Dimer and image test are important for diagnosis and prognosis for COVID-19 patients, which when detected and regulated early, minimize the risks of worsening the case. Final considerations: Therefore, immune suppression and anti-inflammatory drugs are eligible treatments for the cytokine storm, significantly reducing severe cases. In this way, immunomodulators that block interleukin 6 have potential to inhibit in a specific way the hyperinflammation status.
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Ram Kumar, Pandian Sureshbabu, Clayton Fernando Rencilin, and Krishnan Sundar. "Emerging nanomaterials for cancer immunotherapy." Exploration of Medicine 2, no. 3 (June 30, 2021): 208–31. http://dx.doi.org/10.37349/emed.2021.00043.
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Immunotherapy is a unique approach to treat cancer that targets tumours besides triggering the immune cells. It attempts to harness the supremacy and specificity of immune cells for the regression of malignancy. The key strategy of immunotherapy is that it boosts the natural defence and manipulates the immune system at both cellular and molecular levels. Long-lasting anti-tumour response, reduced metastasis, and recurrence can be achieved with immunotherapy than conventional treatments. For example, targeting cytotoxic T-lymphocyte antigen-4 (CTLA4) by monoclonal antibody is reported as an effective strategy against cancer progression in vivo and chimeric antigen receptor (CAR) modified T-cells are known to express a stronger anti-tumour activity. CTLA4 and CAR are, therefore, beneficial in cancer immunotherapy; however, in clinical settings, both are expensive and cause adverse side effects. Nanomaterials have augmented advantages in cancer immunotherapy, besides their utility in effective delivery and diagnostics. In particular, materials based on lipids, polymers, and metals have been sought-after for delivery technologies. Moreover, the surface of nanomaterials can be engineered using ligands, antigens, and antibodies to target immune cells. In this sense, checkpoint inhibitors, cytokines, agonistic antibodies, surface receptors, and engineered T-cells are promising to regulate the immune system against tumours. Therefore, emerging nanomaterials that can be used for the treatment of cancer is the prime focus of this review. The correlation of mode of administration and biodistribution of various nanomaterials is reviewed here. Besides, the acute and chronic side effects and outcome of clinical trials in the context of cancer immunotherapy are discussed.
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Vera Aguilera, Jesus, Courtney L. Erskine, Vera J. Suman, Jonas Paludo, Robert R. McWilliams, Lisa A. Kottschade, Yiyi Yan, et al. "IL-12p40 and MIP3a to predict clinical responses to anti-PD-1 therapy in patients with metastatic melanoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 9535. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.9535.
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9535 Background: A broad understanding of baseline immunity is needed in order to predict responses to PD-1 blockade. We previously reported in a preclinical model that elevated Th1 signature cytokines are present after successful therapy with PD-1 blockade. In this study we evaluated serum cytokines as biomarkers of response in a cohort of patients with metastatic melanoma undergoing anti-PD1 therapy. Methods: 27 pts diagnosed with metastatic melanoma (MM) received anti-PD-1 therapy and had peripheral blood collected prior to anti-PD-1 therapy start and 12 weeks after; 55 proinflammatory-related serum cytokines were analyzed at both times using the Meso Scale Discovery (MSD) assay. At week 12, we identified 15 pts who had radiographic complete or partial response (TR) and 12 had progressive disease (PD) using RECIST criteria. Spearman rank correlation coefficients (rho) were used to assess association between pre-treatment serum cytokine levels. For each cytokine, differences in pretreatment serum levels and the ratio of the 12 week to pre-treatment serum levels between TR and PD groups were assessed using Wilcoxon rank sum tests. Results: Pretreatment serum IL-12p40 and MIP3a (CCL20) were moderately correlated (rho=0.3944). Pretreatment IL-12p40 and was found to be significantly higher (p=0.0025) in the TR group (median=48.5; 25th to 75th percentile [IQR]:25.3-63.8) relative to the PD group (median=17.3; IQR: 8.6-30.3). Pretreatment MIP3a was also found to be significantly higher (p=0.0359) in the TR group (median=1.72; IQR: 1.41-2.65) relative to the PD group (median=1.33; IQR: 1.09-1.98). The 12th week pretreatment IL-12p40 ratio (median=1.98; IQR: 1.4-11.3) in the TR group was greater than that (median=0.64; IQR: 0.23-1.61) in the PD group (p=0.0029); we identified that baseline serum levels >15pg/ml of IL12p40 prior to immunotherapy were associated with significantly prolonged event free survival (p=0.001). Conclusions: Measurements of IL-12p40 and MIP-3a levels before immunotherapy may help to select patients who are likely to benefit from anti-PD1 therapy. Additionally, exploration of combination therapies that increase IL-12P40 and MIP3 prior or during immunotherapy should be undertaken.
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Anand, Namrata, Keng Hee Peh, and Jill M. Kolesar. "Macrophage Repolarization as a Therapeutic Strategy for Osteosarcoma." International Journal of Molecular Sciences 24, no. 3 (February 2, 2023): 2858. http://dx.doi.org/10.3390/ijms24032858.
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Macrophages are versatile immune cells and can adapt to both external stimuli and their surrounding environment. Macrophages are categorized into two major categories; M1 macrophages release pro-inflammatory cytokines and produce protective responses that lead to antimicrobial or antitumor activity. M2 or tumor-associated macrophages (TAM) release anti-inflammatory cytokines that support tumor growth, invasion capacity, and metastatic potential. Since macrophages can be re-polarized from an M2 to an M1 phenotype with a variety of strategies, this has emerged as an innovative anti-cancer approach. Osteosarcoma (OS) is a kind of bone cancer and consists of a complex niche, and immunotherapy is not very effective. Therefore, immediate attention to new strategies is required. We incorporated the recent studies that have used M2-M1 repolarization strategies in the aspect of treating OS cancer.
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Rivera, Ivannie Ortiz, Cristina Iclozan, Andrew McGill, and Tomar Ghansah. "PD-L1/PD-1 Immunotherapy Modulates Effector T Cells Homeostasis and Function in Murine Pancreatic Cancer." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 72.11. http://dx.doi.org/10.4049/jimmunol.196.supp.72.11.
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Abstract Pancreatic Cancer (PC) is one of the most aggressive and deadliest types of cancer, and it is projected to be the second leading cause of cancer-related deaths in the U.S. by the year 2030. PC evades immune surveillance by disrupting the immune homeostasis of effector T cells (Teff). T cells homeostasis is critical for proper anti-tumor immune responses. Preliminary flow cytometry data revealed that murine pancreatic (Panc02) cancer cells produce inflammatory soluble factors and in addition, express Major Histocompatibility Complex class I (MHC-I) and Programmed Death Ligand 1 (PD-L1) and 2 (PD-L2). PD-L1/2 can bind to PD-1 receptors on Teff and induce apoptosis or anergy, dampening the anti-tumor immunity. Cytokine bead array and flow cytometry analysis of serum from peripheral blood from C57BL/6 mice injected with Panc02 cells (TB mice) showed a significant increase in inflammatory factors compared to Control (CTRL) mice. Additionally, Teff from splenocytes from TB mice showed significant reduction in Teff percentages compared to CTRL mice, in vitro. In this study, CD3+ cells from CTRL mice were co-incubated with Panc02 cells pre-treated with anti-PD-L1 antibody (ab) to evaluate the modulation of Teff and cytokines production, in vitro. Mice were inoculated with the Panc02 pre-treated cells with anti-PD-L1 ab, to evaluate the modulation of Teff and cytokines production, in vivo. The results from this project may lead to the identification of new immunotherapeutic strategies to stabilize Teff homeostasis and function that could increase anti-tumor immune responses and combat PC progression.
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Gasser, Stephan, Lina H. K. Lim, and Florence S. G. Cheung. "The role of the tumour microenvironment in immunotherapy." Endocrine-Related Cancer 24, no. 12 (December 2017): T283—T295. http://dx.doi.org/10.1530/erc-17-0146.
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Recent success in immunomodulating strategies in lung cancer and melanoma has prompted much enthusiasm in their potential to treat other advanced solid malignancies. However, their applications have shown variable success and are even ineffective against some tumours. The efficiency of immunotherapies relies on an immunogenic tumour microenvironment. The current field of cancer immunology has focused on understanding the interaction of cancer and host immune cells to break the state of immune tolerance and explain how molecular patterns of cytokines and chemokines affect tumour progression. Here, we review our current knowledge of how inherent properties of tumours and their different tumour microenvironments affect therapeutic outcome. We also discuss insights into recent multimodal therapeutic approaches that target tumour immune evasion and suppression to restore anti-tumour immunity.
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Li, Qiu, Zhihui Hao, Yeting Hong, Wei He, and Wenwen Zhao. "Reprogramming Tumor Associated Macrophage Phenotype by a Polysaccharide from Ilex asprella for Sarcoma Immunotherapy." International Journal of Molecular Sciences 19, no. 12 (November 30, 2018): 3816. http://dx.doi.org/10.3390/ijms19123816.
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We report here the discovery of an acidic polysaccharide, namely IAPS-2, from the root of Ilex asprella, with anti-tumor activity via a repolarizing tumor associated macrophages (TAMs) phenotype. We obtained IAPS-2 polysaccharide from this herb based on acidity and found that IAPS-2 expressed the activity of promoting the secretion of anti-tumor cytokines in macrophages. Furthermore, we evaluated its anti-tumor effect on TAM cells, through the activation of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription (STAT) signaling. In particular, in the tumor murine model, IAPS-2 demonstrated that it could significantly inhibit the growth of tumors via modulating the function of TAMs and increase the animal survival rate. In summary, IAPS-2, with a clearly illustrated chemical composition, potent anti-tumor activity, and a solid mechanism of action, may be developed into a valuable therapeutic tool for cancer immunotherapy.
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Lin, Yu-Ling, and Han-Huei Lin. "Immunotherapeutic effects of RCH-2 on glioblastoma through enhancing NK cellmediated cell lysis." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 58.04. http://dx.doi.org/10.4049/jimmunol.206.supp.58.04.
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Abstract Glioblastoma is the most common and dangerous in primary brain tumors. Recent success in cancer immunotherapy is considered a breakthrough in cancer treatment. RCH-2, a phytocompound isolated from Larrea tridentata, is a transcriptional inhibitor of the Sp1 transcription factor. RCH-2 combined with different chemotherapeutic drugs also shows an excellent synergistic effect for cancer therapy in glioblastoma. RCH-2 effectively inhibits tumor growth in vivo, but less RCH-2 accumulated in the tumor area. RCH-2 might trigger an immune response to help tumor suppression. In this study, glioblastoma tumor-bearing mice were treated with RCH-2 daily by oral administration. Their cytokines and anti-tumor antibodies in sera were analyzed. Results showed that RCH-2 induced Th2 cytokines and promoted anti-tumor antibody production that efficiently induced antibody-dependent cell-mediated cytotoxicity (ADCC) to kill tumor cells. Our finding indicated that RCH-2 could induce more anti-tumor antibodies to efficiently target the tumor cell and trigger NK-mediated cell lysis.
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Kim, Juyang, Hye J. Kim, Jiyoung Kim, Keunhee Park, Hye-Jeong Choi, Hideo Yagita, Hong R. Cho, and Byungsuk Kwon. "Costimulatory Molecule-Targeted Immunotherapy of Chronic Graft-Versus-Host Disease." Blood 108, no. 11 (November 16, 2006): 3236. http://dx.doi.org/10.1182/blood.v108.11.3236.3236.
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Abstract Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. Using the B10.D2àBalb/c (H-2d) minor histocompatibility antigen-mismatched model which reflects clinical and pathological symptoms of human cGVHD, we show that a single injection of an agonistic monoclonal antibody (mAb) to CD137, a member of tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration and alopecia, ultimately leading to prolonged survival. The reversal is associated with markedly reduced helper type 2 CD4+ T cell (Th2) cytokines and increased production of the Th1 cytokine interferon-g (IFN-g). The Fas pathway is required for the therapeutic effect of anti-CD137 mAb on cGVHD. Taken together, these data indicate that anti-CD137 mAb has a therapeutic effect on cGVHD by removing Th2 cells mediating cGVHD. Our study demonstrate an agonistic mAb specific for a costimulatory molecule as a possible target for therapeutic intervention in cGVHD.
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Chan, Godfrey Chi-Fung, and Carol Matias Chan. "Anti-GD2 Directed Immunotherapy for High-Risk and Metastatic Neuroblastoma." Biomolecules 12, no. 3 (February 24, 2022): 358. http://dx.doi.org/10.3390/biom12030358.
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Neuroblastoma is one of the few childhood cancers that carries a tumor-specific antigen in the form of a glycolipid antigen known as GD2. It has restricted expression in normal tissue, such as peripheral afferent nerves. Monoclonal antibodies targeting GD2 have been applied clinically to high-risk neuroblastoma with significant success. However, there are different anti-GD2 products and administration regimens. For example, anti-GD2 has been used in combination with chemotherapy during the induction phase or with retinoic acid during the maintenance stage. Regimens also vary in the choice of whether to add cytokines (i.e., IL-2, GMCSF, or both). Furthermore, the addition of an immune enhancer, such as β-glucan, or allogeneic natural killer cells also becomes a confounder in the interpretation. The question concerning which product or method of administration is superior remains to be determined. So far, most studies agree that adding anti-GD2 to the conventional treatment protocol can achieve better short- to intermediate-term event-free and overall survival, but the long-term efficacy remains to be verified. How to improve its efficacy is another challenge. Late relapse and central nervous system metastasis have emerged as new problems. The methods to overcome the mechanisms related to immune evasion or resistance to immunotherapy represent new challenges to be resolved. The newer anti-GD2 strategies, such as bispecific antibody linking of anti-GD2 with activated T cells or chimeric antigen receptor T cells, are currently under clinical trials, and they may become promising alternatives. The use of anti-GD2/GD3 tumor vaccine is a novel and potential approach to minimizing late relapse. How to induce GD2 expression from tumor cells using the epigenetic approach is a hot topic nowadays. We expect that anti-GD2 treatment can serve as a model for the use of monoclonal antibody immunotherapy against cancers in the future.
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Kim, Hyeyoon, Rira Oh, Ji-Won Heo, Geun Eog Ji, Myeong Soo Park, and Sung-Eun Kim. "Abstract LB532: Bifidobacterium longum RAPO alleviates the risk of immune-related adverse events of anti-PD-1 immunotherapy in a mouse model of triple-negative breast cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB532. http://dx.doi.org/10.1158/1538-7445.am2022-lb532.
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Abstract Background: Triple negative breast cancer (TNBC) has higher risk of early metastasis and recurrence compared with other types of breast cancer. Although immune checkpoint inhibitors (ICIs) have emerged as a feasible strategy for the treatment of TNBC, its use causes various side effects known as immune-related adverse events (irAEs) including pneumonitis, myocarditis, colitis, hepatitis, and nephritis. Considering severe irAEs could lead to ICIs termination and fatal outcomes, studies into immunotherapy that increases anti-tumor efficacy while reducing side effects are needed. We have previously reported that combination therapy of Bifidobacterium longum RAPO and anti-PD-1 shows a better efficacy compared with monotherapy in mice with TNBC. In the present study, we further investigated whether this combination therapy with probiotics would affect the risk of irAEs induced by anti-PD-1 therapy against TNBC. Methods: BALB/c mice bearing the 4T1 murine metastatic breast cancer cells were randomly assigned to tumor control, Bifidobacterium longum RAPO (RAPO), Anti-PD-1, or Anti-PD-1+RAPO group. Tumor tissues were analyzed by Affymetrix Mouse Gene 2.0 ST Array, and functional analysis of microarray data was performed using Ingenuity Pathway Analysis (IPA®, QIAGEN). Lung, heart, colon, liver, and kidney tissues were analyzed by qRT-PCR to determine expression of pro- and anti-inflammatory cytokines. Colon and liver tissues were also analyzed by a Western blot and immunohistochemistry (IHC), respectively. Results: Functional analysis revealed that inflammation in lung and cardiac lesion was predicted to be reduced in Anti-PD-1+RAPO group compared with Anti-PD-1 group. Indeed, expression of pro-inflammatory cytokines including IL1β, IL6, and TNFα was significantly decreased, while anti-inflammatory cytokine IL10 expression was increased in the lung, liver, and kidney tissues of Anti-PD-1+RAPO group compared with Anti-PD-1 group. Similarly, in the heart tissue, TNFα expression was decreased, whereas IL10 was significantly increased in Anti-PD-1+RAPO group than monotherapy group. In the colon tissue, combination therapy of Anti-PD-1 with RAPO significantly enhanced expression of IL10 and tight junction proteins such as occludin and ZO-1 compared with Anti-PD-1 treatment alone. Colonic expression of pro-inflammatory cytokines tended to be reduced in combination therapy group than Anti-PD-1 group. Furthermore, Anti-PD-1+RAPO group was associated with lower level of myeloperoxidase, a pro-inflammatory enzyme released by activated neutrophils, in the liver than Anti-PD-1 group. Conclusions: Collectively, in addition to the effects on anti-tumor efficacy, combination therapy of anti-PD-1 with B. longum RAPO alleviates the risk of irAEs in mice with TNBC. This study provides evidence that B. longum RAPO supplementation might be a novel therapeutic approach in cancer immunotherapy. [This work was supported by BIFIDO Co. and NRF (2020R1C1C1007553 to S-EK).] Citation Format: Hyeyoon Kim, Rira Oh, Ji-Won Heo, Geun Eog Ji, Myeong Soo Park, Sung-Eun Kim. Bifidobacterium longum RAPO alleviates the risk of immune-related adverse events of anti-PD-1 immunotherapy in a mouse model of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB532.
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Jo, Yuna, Laraib Amir Ali, Ju A. Shim, Byung Ha Lee, and Changwan Hong. "Innovative CAR-T Cell Therapy for Solid Tumor; Current Duel between CAR-T Spear and Tumor Shield." Cancers 12, no. 8 (July 28, 2020): 2087. http://dx.doi.org/10.3390/cancers12082087.
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Novel engineered T cells containing chimeric antigen receptors (CAR-T cells) that combine the benefits of antigen recognition and T cell response have been developed, and their effect in the anti-tumor immunotherapy of patients with relapsed/refractory leukemia has been dramatic. Thus, CAR-T cell immunotherapy is rapidly emerging as a new therapy. However, it has limitations that prevent consistency in therapeutic effects in solid tumors, which accounts for over 90% of all cancer patients. Here, we review the literature regarding various obstacles to CAR-T cell immunotherapy for solid tumors, including those that cause CAR-T cell dysfunction in the immunosuppressive tumor microenvironment, such as reactive oxygen species, pH, O2, immunosuppressive cells, cytokines, and metabolites, as well as those that impair cell trafficking into the tumor microenvironment. Next-generation CAR-T cell therapy is currently undergoing clinical trials to overcome these challenges. Therefore, novel approaches to address the challenges faced by CAR-T cell immunotherapy in solid tumors are also discussed here.
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Lin, Gloria Hoi Ying, Yuanqing Liu, Thanuja Ambagala, Byoung S. Kwon, and Tania H. Watts. "Adoptive therapy of a fast growing tumor with reactivated memory T cells combined with anti-4-1BB eliminates tumors through effects of anti-4-1BB on transferred but not host cells (41.37)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 41.37. http://dx.doi.org/10.4049/jimmunol.182.supp.41.37.
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Abstract The ability to expand memory T cells with cytokines ex vivo has greatly increased the practicality of adoptive immunotherapy for cancer. Central memory T cells generated in IL-15 have the advantage of longevity after subsequent in vivo transfer, whereas effector cells have the advantage of more immediate tumor cell killing. Here we report that in adoptive immunotherapy against a pre-established EG.7 tumor, a greater proportion of tumor bearing animals were cured with reactivated memory T cells as compared to animals that received central memory cells. Although central memory cells showed an initial survival advantage in the host, reactivated memory cells expanded more rapidly in the tumor, draining lymph node and spleen, resulting in increased accumulation over time. Co-administration of reactivated memory T cells with anti-4-1BB agonist antibody further potentiated the therapeutic effect. Anti-4-1BB therapy resulted in expansion of host NK, NKT, CD11c+ cells, CD4 and CD8 T cells as well as the adoptively transferred T cells. However, use of 4-1BB-deficient hosts showed that the expression of 4-1BB on adoptively transferred T cells was sufficient for the therapeutic effect. Thus, the combination of reactivated memory T cells and stimulatory anti-41BB antibody represents a superior immunotherapy for a rapidly growing cancer, largely through effects of anti-4-1BB on transferred effector T cells.
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Solinas, Cinzia, Chunyan Gu-Trantien, and Karen Willard-Gallo. "The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy." ESMO Open 5, no. 1 (January 2020): e000544. http://dx.doi.org/10.1136/esmoopen-2019-000544.
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Inducible T cell costimulator (ICOS, cluster of differentiation (CD278)) is an activating costimulatory immune checkpoint expressed on activated T cells. Its ligand, ICOSL is expressed on antigen-presenting cells and somatic cells, including tumour cells in the tumour microenvironment. ICOS and ICOSL expression is linked to the release of soluble factors (cytokines), induced by activation of the immune response. ICOS and ICOSL binding generates various activities among the diversity of T cell subpopulations, including T cell activation and effector functions and when sustained also suppressive activities mediated by regulatory T cells. This dual role in both antitumour and protumour activities makes targeting the ICOS/ICOSL pathway attractive for enhancement of antitumour immune responses. This review summarises the biological background and rationale for targeting ICOS/ICOSL in cancer together with an overview of the principal ongoing clinical trials that are testing it in combination with anti-cytotoxic T lymphocyte antigen-4 and anti-programmed cell death-1 or anti-programmed cell death ligand-1 based immune checkpoint blockade.
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Floris, Ilaria, Thorsten Rose, Juan Antonio Collado Rojas, Kurt Appel, Camille Roesch, and Beatrice Lejeune. "Pro-Inflammatory Cytokines at Ultra-Low Dose Exert Anti-Inflammatory Effect In Vitro: A Possible Mode of Action Involving Sub-Micron Particles?" Dose-Response 18, no. 4 (October 1, 2020): 155932582096172. http://dx.doi.org/10.1177/1559325820961723.
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Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are pro-inflammatory cytokines involved in acute and chronic inflammatory diseases. Indeed, immunotherapy blocking these 2 cytokines has been developed. Micro-immunotherapy (MI) also uses ultra-low doses (ULD) of pro-inflammatory cytokines, impregnated on lactose-sucrose pillules, to counteract their overexpression. The study has been conducted with 2 objectives: examine the anti-inflammatory effect in vitro and the capacity of 2 unitary medicines, TNF-α (27 CH) and IL-1β (27 CH), to reduce the secretion of TNF-α in human primary monocytes and THP-1 cells differentiated with phorbol-12-myristate-13-acetate, after lipopolysaccharide (LPS) exposure; then, investigate the presence of particles possibly containing starting materials using tunable resistive pulse sensing technique. The results show that the unitary medicines, tested at 3 pillules concentrations (5.5, 11 and 22 mM), have reduced the secretion of TNF-α in both models by about 10−20% vs. vehicle control, depending on concentration. In this exploratory study, particles (150−1000 nm) have been detected in MI ULD-impregnated pillules and a hypothesis for MI medicines mode of action has been proposed. Conscious that more evaluations are necessary, authors are cautious in the conclusions because the findings described in the study are still limited, and future investigations may lead to different hypothesis.
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Veigas, Florencia, Yamil D. Mahmoud, Ana Flores, Rosa Morales, Sabrina Gatto, Juan Manuel Perez Saez, Elmer Fernandez, Gabriel A. Rabinovich, and María Romina Girotti. "Characterization of the immune microenvironment in melanoma patients resistant to targeted and immunotherapies by a multidisciplinary approach." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 241.41. http://dx.doi.org/10.4049/jimmunol.204.supp.241.41.
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Abstract Most melanoma patients who develop resistance to targeted therapies do not respond to subsequent immunotherapy. Therefore, establishing which patients would derive clinical benefit from immunotherapy is a compelling clinical question. We performed a meta-analysis of published transcriptome datasets from melanoma biopsies before and after development of resistance to BRAFi or BRAFi/MEKi. We observed an increase in M2-macrophages infiltrate by CIBERSORT in relapsed biopsies as well as an increase in T-cell exhaustion markers and immunosuppressive cytokines. Our preliminary findings show changes in the galectin/glycan axis in melanoma resistance to BRAFi/MEKi. Particularly, we observed that the expression of Galectin-1 (Gal-1) is increased in human melanoma resistant cells. We analyzed single-cell and bulk RNA-Seq gene expression profiles from melanoma biopsies before and during treatment with anti-PD-1/anti-CTLA-4 and found that macrophages and CD8 T-cells of non-responders upregulate a specific glycosylation-related signature. Macrophages from non-responding patients show an immunosuppressive expression profile accompanied by the appearance of a novel sub-group during treatment associated with resistance. We hypothesize that there are Gal-1/glycan interactions that promote an M2 immunosuppressive microenvironment in resistant tumors preventing response to immunotherapy. Finally, we developed MIXTURE, a novel algorithm to infer the tumor immune infiltrate that overcomes CIBERSORT limitations. MIXTURE analysis revealed a differential immunosuppressive infiltrate in melanoma biopsies with high intratumoral heterogeneity and in biopsies from non-responding patients to anti PD-1 immunotherapy.
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Allard, Bertrand, Martin Turcotte, and John Stagg. "CD73-Generated Adenosine: Orchestrating the Tumor-Stroma Interplay to Promote Cancer Growth." Journal of Biomedicine and Biotechnology 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/485156.
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Despite the coming of age of cancer immunotherapy, clinical benefits are still modest. An important barrier to successful cancer immunotherapy is that tumors employ a number of mechanisms to facilitate immune escape, including the production of anti-inflammatory cytokines, the recruitment of regulatory immune subsets, and the production of immunosuppressive metabolites. Significant therapeutic opportunity exists in targeting these immunosuppressive pathways. One such immunosuppressive pathway is the production of extracellular adenosine by CD73, an ectonucleotidase overexpressed in various types of cancer. We hereafter review the biology of CD73 and its role in cancer progression and metastasis. We describe the role of extracellular adenosine in promoting tumor growth through paracrine and autocrine action on tumor cells, endothelial cells, and immune cells.
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Oechsle, Crystal M., Loral E. Showalter, Colleen M. Novak, Brain J. Czerniecki, and Gary K. Koski. "Statin Drugs Plus Th1 Cytokines Potentiate Apoptosis and Ras Delocalization in Human Breast Cancer Lines and Combine with Dendritic Cell-Based Immunotherapy to Suppress Tumor Growth in a Mouse Model of HER-2pos Disease." Vaccines 8, no. 1 (February 6, 2020): 72. http://dx.doi.org/10.3390/vaccines8010072.
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A dendritic cell-based, Type 1 Helper T cell (Th1)-polarizing anti-Human Epidermal Growth Factor Receptor-2 (HER-2) vaccine supplied in the neoadjuvant setting eliminates disease in up to 30% of recipients with HER-2-positive (HER-2pos) ductal carcinoma in situ (DCIS). We hypothesized that drugs with low toxicity profiles that target signaling pathways critical for oncogenesis may work in conjunction with vaccine-induced immune effector mechanisms to improve efficacy while minimizing side effects. In this study, a panel of four phenotypically diverse human breast cancer lines were exposed in vitro to the combination of Th1 cytokines Interferon-gamma (IFN-γ) and Tumor Necrosis Factor-alpha (TNF-α) and lipophilic statins. This combination was shown to potentiate multiple markers of apoptotic cell death. The combination of statin drugs and Th1 cytokines minimized membrane K-Ras localization while maximizing levels in the cytoplasm, suggesting a possible means by which cytokines and statin drugs might cooperate to maximize cell death. A combined therapy was also tested in vivo through an orthotopic murine model using the neu-transgenic TUBO mammary carcinoma line. We showed that the combination of HER-2 peptide-pulsed dendritic cell (DC)-based immunotherapy and simvastatin, but not single agents, significantly suppressed tumor growth. Consistent with a Th1 cytokine-dependent mechanism, parenterally administered recombinant IFN-γ could substitute for DC-based immunotherapy, likewise inhibiting tumor growth when combined with simvastatin. These studies show that statin drugs can amplify a DC-induced effector mechanism to improve anti-tumor activity.
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Thadi, Anusha, Marian Khalili, William Morano, Scott Richard, Steven Katz, and Wilbur Bowne. "Early Investigations and Recent Advances in Intraperitoneal Immunotherapy for Peritoneal Metastasis." Vaccines 6, no. 3 (August 10, 2018): 54. http://dx.doi.org/10.3390/vaccines6030054.
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Peritoneal metastasis (PM) is an advanced stage malignancy largely refractory to modern therapy. Intraperitoneal (IP) immunotherapy offers a novel approach for the control of regional disease of the peritoneal cavity by breaking immune tolerance. These strategies include heightening T-cell response and vaccine induction of anti-cancer memory against tumor-associated antigens. Early investigations with chimeric antigen receptor T cells (CAR-T cells), vaccine-based therapies, dendritic cells (DCs) in combination with pro-inflammatory cytokines and natural killer cells (NKs), adoptive cell transfer, and immune checkpoint inhibitors represent significant advances in the treatment of PM. IP delivery of CAR-T cells has shown demonstrable suppression of tumors expressing carcinoembryonic antigen. This response was enhanced when IP injected CAR-T cells were combined with anti-PD-L1 or anti-Gr1. Similarly, CAR-T cells against folate receptor α expressing tumors improved T-cell tumor localization and survival when combined with CD137 co-stimulatory signaling. Moreover, IP immunotherapy with catumaxomab, a trifunctional antibody approved in Europe, targets epithelial cell adhesion molecule (EpCAM) and has shown considerable promise with control of malignant ascites. Herein, we discuss immunologic approaches under investigation for treatment of PM.
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McDuffie, Robert S., and Ronald S. Gibbs. "Animal Models of Ascending Genital-Tract Infection in Pregnancy." Infectious Diseases in Obstetrics and Gynecology 2, no. 2 (1994): 60–70. http://dx.doi.org/10.1155/s1064744994000414.
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This article reviews animal models currently used for investigation of ascending genital-tract infection in pregnancy. The specific models reviewed are those in the rabbit, monkey, and mouse. These models investigate both the direct effects of bacteria in the setting of ascending infection and the role of cytokines produced by the immune system. For each model, experiments that delineate the pathophysiology of ascending genital-tract infection in pregnancy are described. Intervention experiments, including the use of antibiotics, anti-inflammatory agents, immunotherapy, and anti-cytokine therapy, are described. Comparison of these models is made with respect to pathogenesis in humans, reproducibility, anatomy, and cost.
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Heller, Richard, Cathryn M. Lundberg, Niculina Burcus, Chelsea Edelblute, and Siqi Guo. "Gene electrotransfer of plasmids encoding cytokines as an effective immunotherapy approach for melanoma." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 213.16. http://dx.doi.org/10.4049/jimmunol.196.supp.213.16.
Full textAbstract:
Abstract Gene electrotransfer (GET) of plasmids encoding cytokines has been shown to generate a potent anti-tumor effect. Effective protocols have been developed delivering the plasmids directly into tumors. To obtain an effective immune response, it is critical to achieve a balance between transgene expression and tissue damage. GET is a reliable and effective physical method for in vivo delivery of plasmid DNA. It is particularly attractive for use in anti-cancer cytokine therapy as it does not incur the side effects associated with conventional protein cytokine therapy. Delivery of plasmids encoding cytokines directly to tumors has been shown by our lab and others to induce not only local immune response, but a systemic one as well. The positive responses were directly related to the ability to achieve the appropriate expression profile following delivery of the plasmid. Interestingly, the electrotransfer parameters were dependent on which cytokine was being delivered. For plasmid encoding IL-12 the correct parameters were 1300 V/cm and 100 us. For IL-15, the appropriate parameters were 600 V/cm and 5 ms. The procedure included injecting the plasmid DNA into established B16.F10 melanoma tumors of C57BL/6 mice and electric pulses applied three times over a one week period. To enhance this immune response, current work is further analyzing the immune response to determine if there is a marker that would indicate appropriate delivery of the plasmid. In addition, combination therapies are being explored to evaluate if the response could be augmented. A more complete understanding of the process and identifying other agents that could further augment this approach would be an important step.
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Shute, Travis J., Elizabeth Dudley, Andrew Lai, Briana Salas, Daniel Angel, Kelly Nash, and Elizabeth Leadbetter. "Glycolipid-loaded nanoparticles harness iNKT cells for tumor immunotherapy." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 246.22. http://dx.doi.org/10.4049/jimmunol.204.supp.246.22.
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Abstract Invariant natural killer T cells (iNKT) have a well-documented role in anti-tumor immunity through their release of proinflammatory cytokines and cytotoxic compounds. As iNKT cells can have direct and indirect killing effects on tumor cells, we propose a novel strategy for activating iNKT cells, via a PLGA nanoparticle delivery platform, to promote anti-tumor immune responses. Poly-lactic-co-glycolic acid (PLGA) nanoparticles can be reproducibly loaded with an iNKT cell glycolipid agonist, alpha-galactosylceramide (αGalCer), and a tumor associated antigen, ovalbumin (OVA). These dual-loaded PLGA nanoparticles rapidly activate iNKT cells in vivo to produce IFNgamma. Furthermore, in an in vivo model of melanoma, using B16F10-OVA cells, both prophylactic and therapeutic administration of nanoparticles containing αGalCer and OVA led to decreased tumor cell growth and increased survival. Ongoing studies are extending these concepts to PLGA nanoparticles loaded with αGalCer plus an immunogenic peptide from the naturally expressed melanocyte protein glycoprotein 100, gp100 25-33. This novel delivery system provides a platform with tremendous potential to harness iNKT cells for cancer immunotherapy purposes and as part of combinational therapies with other approaches such as checkpoint inhibitors.
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Kim, Juyang, Hye J. Kim, Keunhee Park, Jiyoung Kim, Hye Jeong Choi, Hideo Yagita, Seok H. Nam, Hong R. Cho, and Byungsuk Kwon. "Costimulatory molecule-targeted immunotherapy of chronic graft-versus-host disease (88.17)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S141—S142. http://dx.doi.org/10.4049/jimmunol.178.supp.88.17.
Full textAbstract:
Abstract Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. Using the B10.D2„³Balb/c (H-2d) minor histocompatibility antigen-mismatched model which reflects clinical and pathological symptoms of human cGVHD, we show that a single injection of an agonistic monoclonal antibody (mAb) to CD137, a member of tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration and alopecia, ultimately improving general health conditions. The reversal is associated with markedly reduced CD4+ T cell cytokines and increased apoptosis of donor CD4+ T cells. The Fas pathway is required for the therapeutic effect of anti-CD137 mAb on cGVHD. Taken together, these data indicate that anti-CD137 mAb has a therapeutic effect on cGVHD by removing donor CD4+ T cells mediating cGVHD. Our study demonstrates an agonistic mAb specific for a costimulatory molecule as a possible target for therapeutic intervention in cGVHD.
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Kim, Juyang, Hye J. Kim, Keunhee Park, Jiyoung Kim, Hye-Jeong Choi, Hideo Yagita, Seok H. Nam, Hong R. Cho, and Byungsuk Kwon. "Costimulatory molecule-targeted immunotherapy of cutaneous graft-versus-host disease." Blood 110, no. 2 (July 15, 2007): 776–82. http://dx.doi.org/10.1182/blood-2006-08-043612.
Full textAbstract:
Abstract Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. The B10.D2→Balb/c (H-2d) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD, was used in this study. We demonstrated that a single injection of an agonistic monoclonal antibody (mAb) against CD137, a member of the tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration, and alopecia, a dominant feature of cGVHD (cutaneous GVHD), ultimately improving general health conditions. The reversal is associated with markedly reduced CD4+ T-cell cytokines and increased apoptosis of donor CD4+ T cells. The Fas pathway is required for ameliorating cutaneous GVHD by anti-CD137 mAb. Taken together, these data indicate that the anti-CD137 mAb has a therapeutic effect on cutaneous GVHD by removing donor CD4+ T cells that cause cutaneous GVHD. Thus, our study demonstrates an agonistic mAb, specific for a costimulatory molecule, as a possible target for therapeutic intervention in cutaneous GVHD.