Enhancing T Cell Therapy of Cancer

但前提是。 使用基因改变的自体T细胞治疗癌症提供了肿瘤特异性的潜在好处 与传统的放化疗或同种异体肝移植的过继治疗相比，减少和减少毒性 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 肿瘤细胞的逃避策略，如分泌抑制分子转化生长因子-β。因此，在扩展之后 高免疫原性肿瘤治疗霍奇金病及其他低免疫原性肿瘤的研究进展 (1-4年)，该计划项目将把重点转移到设计、评估和临床实施 对抗免疫调节负面影响和改善活化的贩运的战略 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 在三个核心服务(CELL)支持的四个研究项目中进行的临床前和临床研究 加工、病媒制造、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。可以绕过主动和被动的免疫逃避吗？ 让肿瘤逃脱T细胞反应的策略？有没有可能调节肿瘤的微环境 以确保最佳的T细胞功能？输注的CTL对肿瘤部位的归巢能否优化？调查人员在 项目1将测试引入显性负向转化生长因子-βII型受体是否对肿瘤特异性 CTL将使细胞对转化生长因子-β的不利影响产生抵抗。在项目2中，重点是 会对CD4+CD25+调节性T细胞(Tregs)的微环境及其是否阴性 Toll样配体治疗可逆转对肿瘤疫苗和CTL治疗的影响 感受器。项目3的主旨将是确定异源趋化因子的引入 受体进入神经母细胞瘤特异性效应T细胞)可以促进它们向肿瘤部位的转运。最后，在 项目4，研究人员将尝试改进针对EBV的CTL疗法的有希望的结果 通过输注具有多种抗肿瘤特异性的T细胞来降低鼻咽癌的肿瘤风险 通过抗原调节逃逸。为这项研究计划选定的所有研究人员都证明了 在癌症免疫学、细胞治疗临床试验、EB病毒病毒学和动物研究方面的专长 模特们。这一背景，加上项目负责人之间的长期合作，预示着 在下一个供资周期内广泛的、可能是协同作用的相互作用。 Lay概要-免疫疗法作为一种有效的癌症治疗方法前景广阔。但为了这个承诺 要实现这一目标，必须克服某些障碍。这项研究项目的研究人员将试图 对抗肿瘤细胞使用的几种最常见的免疫逃避策略

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