Enhancing T Cell Therapy of Cancer

增强癌症 T 细胞治疗

• 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
• 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

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

提供了 使用基因改变的自体T细胞的癌症治疗提供了肿瘤特异性免疫调节的潜在益处。 与常规放化疗或采用同种异体移植物的过继疗法相比， T细胞。即便如此，一些障碍可能会限制这种治疗的有效性，包括免疫系统。 肿瘤细胞的逃避策略，如抑制性分子TGF-β的分泌。因此，在扩展 高免疫原性肿瘤对霍奇金病和其他低免疫原性肿瘤的治疗进展 （1-4年），该计划项目将重点转移到设计，评估和临床实施， 对抗负面免疫调节影响和改善活化的 细胞毒性T淋巴细胞（CTL）对肿瘤沉积物的作用。这一长期目标将通过一系列迭代来实现。 临床前和临床研究在四个研究项目中进行，由三个核心服务（Cell 加工、载体生产、行政/监管/生物统计）。这项研究计划是 旨在解决三个核心问题。一个人能规避主动和被动免疫逃避吗 让肿瘤逃避T细胞反应的策略有没有可能调节肿瘤微环境 以确保最佳的T细胞功能可以优化输注的CTL到肿瘤部位的归巢吗？调查人员 项目1将测试是否引入显性负性TGF-β II型受体对肿瘤特异性 CTL将使细胞抵抗TGF-β的不利影响。在项目2中， 将对微环境中的CD 4 + CD 25+调节性T细胞（TCRs）以及它们的阴性 对癌症疫苗和CTL治疗影响可通过Toll样配体治疗逆转 受体。项目3的重点将是确定是否引入异源趋化因子 受体进入成神经细胞瘤特异性效应T细胞）可以增强它们向肿瘤部位的运输。最后在 项目4，研究人员将尝试用靶向EBV的CTL治疗来改善他们有希望的结果 通过输注具有多种抗肿瘤特异性的T细胞， 通过抗原调节来逃避。所有被选入本研究项目的研究人员都证明了 在癌症免疫学、细胞治疗临床试验、EBV病毒学和动物研究方面的专业知识 模型这一背景，加上项目领导人之间的长期合作，预测 在下一个供资周期内进行广泛的、可能具有协同作用的互动。 免疫疗法作为一种有效的癌症治疗方法有很大的希望。但为了这个承诺 要实现这一目标，就必须克服某些障碍。这项研究计划的研究人员将试图 对抗肿瘤细胞使用的几种最常见的免疫逃避策略