Homeostatic proliferation and regulatory T cell depletion as cancer immunotherapy

稳态增殖和调节性 T 细胞耗竭作为癌症免疫疗法

• 批准号: 8097593
• 负责人: JUSTIN P. KLINE
• 金额: $ 12.98万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097593
• 关键词: Adoptive Immunotherapy; Adoptive Transfer; Antigens; Autoimmune Process; Autoimmunity; Autologous; Award; Blood; Blood specimen; Cancer Patient; Cell Proliferation; Cell Therapy; Cell physiology; Clinical; Clinical Data; Clinical Trials; Colitis; Data; Development; Dioxygenases; Disease; Dose; Effectiveness; Engineering; Enrollment; Environment; Enzymes; Flow Cytometry; Future; Goals; Hepatitis; IL2RA gene; Image; Immune; Immune response; Immune system; Immunotherapeutic agent; Intervention; Kinetics; Laboratories; Lymphocyte Subset; Lymphopenia; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Mus; Outcome; Patients; Peptides; Phase; Phase I Clinical Trials; Population; Pre-Clinical Model; Principal Investigator; Procedures; Process; Production; Proliferating; Proliferation Marker; Public Health; Recovery; Regulatory Pathway; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Resistance; Role; Safety; Sampling; Site; Stromal Cells; T cell anergy; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Training; Tryptophan; Tumor Escape; Up-Regulation; Vaccination; Vaccines; Vitiligo; Whole-Body Irradiation; cancer cell; cancer immunotherapy; career; clinical efficacy; combinatorial; graft vs host disease; improved; indole-2,3-dioxygenase; indoleamine; neoplastic cell; novel; novel strategies; peripheral blood; pre-clinical; prevent; programs; receptor; response; tumor

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.

描述（由申请人提供）：大量证据表明，免疫系统，特别是T细胞，可以识别和破坏恶性细胞。然而，尽管肿瘤特异性T细胞的充分引发，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，当这些机制被逆转时，可以改善抗肿瘤反应。在小鼠过继性免疫治疗模型中，Kline博士采取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细胞无反应性可以通过淋巴细胞减少诱导的稳态增殖过程逆转，并且可以在大量T细胞过继转移到淋巴细胞减少宿主中之前去除调节性T细胞。当稳态增殖与调节性T细胞耗竭相结合时，发生有效的肿瘤排斥。这些结果促使Kline博士开发了一项I期方案，以测试这种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在诱导癌症患者淋巴细胞减少症方面的有效性，并确定在转移到此类照射宿主中后，缺乏调节性T细胞的自体多克隆T细胞是否发生稳态增殖。将继续进行安全性分析，特别是关注自身免疫性。另一个目标是确定这种方法是否与客观肿瘤缓解相关。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型癌症免疫策略的方式产生重大影响。最后，其他抑制肿瘤逃逸机制的继续探索将在实验室环境中进行。总的来说，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，并且结果普遍较差。Kline博士在临床和基础科研方面的早期培训得到了加强，他希望能够为转化癌症免疫治疗研究的职业生涯建立必要的专业知识。