Enhancing T Cell Therapy of Cancer

增强癌症 T 细胞治疗

基本信息

批准号：
7845205
负责人：
HELEN E HESLOP
金额：
$ 5.94万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845205
关键词：
Address Adoptive Transfer Adverse effects Aftercare Allogenic Animal Model Antigen Targeting Antigenic Modulation Autoantigens Autologous Autologous Stem Cell Transplantation Biological Biometry Cancer Immunology Science Cancer Vaccines Cell Survival Cell Therapy Cell physiology Cells Chronic Myeloid Leukemia Clinical Clinical Research Clinical Trials Collaborations Complex Cytotoxic T-Lymphocytes Data Deposition Development Disease remission Dominant-Negative Mutation Donor Lymphocyte Infusion EBV-Specific Cytotoxic T-Lymphocyte Effectiveness Epstein Barr Nuclear Antigen 3 Epstein-Barr Virus latency Face Failure Funding Genetic Goals Grant Growth Health Benefit Hodgkin Disease Homing Human Herpesvirus 4 IL2RA gene Immune Immune response Immune system Immunity Immunocompetent Immunocompromised Host Immunotherapy Infusion procedures Investigation Laboratories Ligands Link Lymphoma Malignant Neoplasms Modification Molecular Monoclonal Antibody Therapy Neuroblastoma Newly Diagnosed Nuclear Pore Complex Oncologist Orphan Drugs Patients Progress Reports Proteins Public Health Radiation Recurrent disease Recurrent tumor Relapse Relative (related person)Reliance Research Research Personnel Research Project Grants Resistance Retroviral Vector Risk Secure Series Services Site Specificity Stem cell transplant System T-Lymphocyte Testing Therapeutic Toll-like receptors Toxic effect Transforming Growth Factor beta Translating Transplantation Treatment Protocols Treatment outcome Tumor Antigens Tumor Escape Tumor Expansion Variant Viral Antigens Virus Diseases base cancer immunotherapy cancer therapy chemokine chemokine receptor chemotherapy combat cytotoxic design human TGFBR2 protein immunogenic immunosuppressed improved in vivo insight neoplastic cell pre-clinical prevent programs receptor research clinical testing response trafficking treatment strategy tumor tumor growth vector virology

项目摘要

PROVIDED. ancer therapy using genetically altered autologous T cells offers the potential benefit of tumor-specific <illing and decreased toxicity relative to conventional chemoradiotherapy or adoptive therapy with allogeneic T cells. Even so, a number of obstacles can limit the effectiveness of such treatment, including the immune evasion tactics of tumor cells, such as secretion of the inhibitory molecule TGF-beta. Thus, after extending therapeutic advances in highly immunogenic tumors to Hodgkin disease and other less immunogenic tumors (Years 1-4), this program project will shift its focus to the design, evaluation and clinical implementation of strategies to counteract negative immunoregulatory influences and to improve the trafficking of activated cytotoxic T lymphocytes (CTLs) to tumor deposits. This long-term goal will be pursued in a series of iterative preclinical and clinical studies conducted within four research projects supported by three core services (Cell Processing, Vector Manufacturing, Administrative/Regulatory/Biostatistics). This plan of research was devised to address three central questions. Can one circumvent the active and passive immune evasion tactics that allow tumors to escape T-cell responses? Is it possible to modulate the tumor microenvironment to secure optimal T-cell function? Can homing of infused CTLs to tumor sites be optimized? Investigators in Project 1 will test whether the introduction of a dominant negative TGF-beta type II receptor on tumorspecific CTLs will render the cells resistant to the adverse effects of TGF-beta. In Project 2 the emphasis will be on CD4+ CD25+ regulatory T cells (Tregs) in the microenvironment and whether their negative influence on cancer vaccines and CTL therapy can be reversed by treatment with ligands for Toll-like receptors. The thrust of Project 3 will be to determine if the introduction of heterologous chemokine receptors into neuroblastoma-specific effector T cells) can enhance their trafficking to tumor sites. Finally, in Project 4, the investigators will attempt to improve on their promising results with CTL therapy targeting EBV antigens in NPC by infusing T cells that harbor multiple antitumor specificities to reduce the risk of tumor escape by antigenic modulation. All investigators selected for this research program have demonstrated expertise in cancer immunology, clinical trials of cellular therapy, EBV virology and investigations with animal models. This background, together with long-standing collaborations among the project leaders, predicts extensive, possibly synergistic, interactions over thejnext funding cycle. Lay summary - Immunotherapy holds much promise as an effective cancer treatment. But for this promise to be realized, certain obstacles must be overcome. Investigators in this research program will attempt to combat several of the most common immune evasion strategies used by tumor cells

假如。使用遗传改变自体T细胞的ANCER疗法为肿瘤特异性的潜在益处 <相对于常规化学放疗或同种异体疗法的毒性降低和降低 T细胞。即使这样，许多障碍可能会限制这种治疗的有效性，包括免疫肿瘤细胞的逃避策略，例如抑制性分子TGF-β的分泌。因此，延伸后高度免疫原性肿瘤对霍奇金病和其他免疫原性肿瘤的治疗进展（1 - 4年），该计划项目将把重点转移到设计，评估和临床实施中抵消负面免疫调节影响并改善激活的贩运的策略细胞毒性T淋巴细胞（CTL）至肿瘤沉积物。这个长期目标将在一系列迭代中实现在四个核心服务支持的四个研究项目中进行的临床前和临床研究（细胞处理，矢量制造，行政/监管/生物统计学）。这项研究计划是设计用于解决三个中心问题。一个人可以绕开主动和被动免疫逃避允许肿瘤逃脱T细胞反应的战术？是否可以调节肿瘤微环境确保最佳的T细胞功能？可以优化将注入的CTL归入肿瘤部位吗？调查人员在项目1将测试是否引入特定于肿瘤的负TGF-beta II型受体 CTL将使细胞对TGF-β的不良反应有抵抗力。在项目2中重点将在微环境中的CD4+ CD25+调节T细胞（Tregs）上对癌症疫苗和CTL治疗的影响可以通过用Toll样的配体治疗来逆转受体。项目3的推力是确定是否引入异源趋化因子进入神经母细胞瘤特异性效应T细胞的受体可以增强其对肿瘤部位的运输。最后，在项目4，调查人员将尝试通过针对EBV的CTL治疗来改善其有希望的结果 NPC中的抗原通过注入带有多种抗肿瘤特异性的T细胞来降低肿瘤的风险通过抗原调节逃脱。所有为该研究计划选出的研究人员都证明了癌症免疫学专业知识，细胞疗法的临床试验，EBV病毒学和动物研究型号。这种背景以及项目负责人之间的长期合作预测广泛的，可能是协同的交互作用，在融资周期中。 LIE摘要 - 免疫疗法作为一种有效的癌症治疗有很大的希望。但是为了这个诺言要实现，必须克服某些障碍。该研究计划中的调查人员将尝试对抗肿瘤细胞使用的几种最常见的免疫逃避策略