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，可以识别并摧毁恶性细胞。然而，尽管有足够的肿瘤特异性T细胞启动，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。这些观察结果表明，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，抗肿瘤反应就会得到改善。在小鼠过继免疫治疗模型中，Kline博士寻求策略来逆转两种假定的抑制机制：T细胞能量和调节性T细胞。他发现T细胞的能量可以通过淋巴细胞减少诱导的稳态增殖过程逆转，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。当稳态增殖与调节性T细胞耗竭相结合时，会发生强烈的肿瘤排斥反应。这些结果促使Kline博士开发了一项I期协议，以测试该策略在癌症患者中的有效性。在拟议的奖励期间，Kline博士建议研究全身照射诱导癌症患者淋巴细胞减少的有效性，并确定在转移到受照射的宿主后，是否会发生缺乏调节性T细胞的自体多克隆T细胞的稳态增殖。将对安全性进行分析，特别是对自身免疫的分析。另一个目标是确定这种方法是否与客观肿瘤反应有关。这项研究如果成功，可以作为未来临床试验的平台，并可能对开发和交付新型癌症免疫治疗策略的方式产生重大影响。最后，将在实验室环境中继续探索其他抑制肿瘤逃逸机制。总的来说，这项研究可能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，而且结果普遍较差。通过早期临床和基础科学研究方面的培训，Kline博士希望在转化性癌症免疫治疗研究方面建立必要的专业知识。

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.