Homeostatic proliferation and regulatory T cell depletion as cancer immunotherapy

描述(由申请人提供)：大量证据表明，免疫系统，特别是T细胞，可以识别和摧毁恶性细胞。然而，尽管肿瘤特异性T细胞被充分激发，但迄今为止在疫苗或过继细胞治疗试验中很少发生肿瘤消退。这些观察表明，肿瘤微环境中的免疫抑制机制可能占主导地位，并允许肿瘤逃逸。研究表明，当这种机制被逆转时，可以改善抗肿瘤反应。在小鼠过继免疫治疗模型中，克莱恩博士寻求了逆转两种假定的抑制机制的策略：T细胞无能和调节性T细胞。他发现，T细胞无能可以通过淋巴细胞减少诱导的稳态增殖过程被逆转，并且调节性T细胞可以在大量T细胞过继转移到淋巴细胞减少的宿主之前被移除。当体内平衡增殖与调节性T细胞耗尽相结合时，就会发生强大的肿瘤排斥反应。这些结果促使克莱恩博士制定了一项I期方案，以测试该策略在癌症患者中的有效性。在建议的获奖期内，克莱恩博士建议调查全身照射在癌症患者中诱导淋巴细胞减少的有效性，并确定缺乏调节性T细胞的自体多克隆T细胞在转移到此类照射宿主后是否会发生稳态增殖。将继续进行安全性分析，特别是对自身免疫性的分析。另一个目标是确定这种方法是否与客观的肿瘤反应有关。这项研究如果成功，可以作为未来临床试验的平台，并可能对开发和提供新的癌症免疫治疗策略的方式产生重大影响。最后，将在实验室中继续探索其他抑制肿瘤逃逸的机制。总体而言，这项研究可能会产生对公共卫生具有重要影响的重大发现，因为它可能为晚期恶性疾病患者的治疗提供一种新的方法，否则这些患者的治疗选择有限，结果普遍较差。在加强临床和基础科学研究早期培训的基础上，克莱恩博士希望积累转化型癌症免疫治疗研究事业所需的必要专业知识。

DESCRIPTION (provided by applicant): A wealth of evidence suggests that the immune system, specifically T cells, can recognize and destroy malignant cells. However, despite adequate priming of tumor-specific T cells, tumor regression has rarely occurred in vaccine or adoptive cell therapy trials to date. These observations suggest that immune suppressive mechanisms in the tumor microenvironment may dominate and allow tumor escape. Research suggests that when such mechanisms are reversed, improved anti-tumor responses can occur. In a murine adoptive immunotherapy model, Dr. Kline has pursued strategies to reverse two putative inhibitory mechanisms: T cell anergy and regulatory T cells. He has found that T cell anergy can be reversed through the process of lymphopenia-induced homeostatic proliferation and that regulatory T cells can be removed prior to the adoptive transfer of bulk T cells into lymphopenic hosts. When homeostatic proliferation is combined with regulatory T cell depletion, potent tumor rejection occurs. These results have prompted Dr. Kline to develop a phase I protocol to test the effectiveness of this strategy in cancer patients. During the proposed award period, Dr. Kline proposes to investigate the effectiveness of total body irradiation in inducing lymphopenia in cancer patients, and to determine whether homeostatic proliferation of autologous polyclonal T cells depleted of regulatory T cells occurs following transfer into such irradiated hosts. Analysis of safety, in particular focusing on autoimmunity, will be pursued. An additional goal is to determine if this approach is associated with objective tumor responses. This research, if successful, could serve as a platform for future clinical trials and may have a significant impact on the way in which novel cancer immunotherapeutic strategies are developed and delivered. Lastly, a continued exploration of other inhibitory tumor escape mechanisms will ensue in the laboratory setting. Overall, this research may generate significant findings with important ramifications to public health, as it may offer a new approach to the treatment of patients with advance malignant diseases, who otherwise have a limited number of therapeutic options, and a universally poor outcome. Enhancing on his early training in both clinical and basic scientific research, Dr. Kline expects to build the necessary expertise required for a career in translational cancer immunotherapy research.