Adoptive Cell Therapy with Rejuvenated Antigen-Specific T Cells

 描述(由申请人提供)：黑色素瘤的发病率在全球范围内不断增加，由于治疗选择有限，晚期或转移性黑色素瘤患者的预后仍然很差。抗原特异性CD8+T细胞过继细胞治疗(ACT)是治疗慢性病毒感染和包括黑色素瘤在内的多种恶性肿瘤的一种有前途的方法。ACT的一个主要局限性是输注后T细胞在体内的存活率很低。具有较长端粒的分化较低的T细胞是基于ACT的免疫治疗的理想T细胞亚群(被称为高亲和力T细胞)；然而，产生大量的这种“年轻”T细胞是有问题的。这一局限性可以通过使用诱导多能干细胞(IPSCs)作为针对靶向抗原的T细胞的无限来源来克服。从人T细胞来源的IPSCs分化出的T细胞具有较长的端粒，并在体外表现出抗原特异性的杀伤效应。尽管有这些发现，但我们对使用IPSC来源的T细胞进行ACT的体内安全性和治疗效果的了解还存在差距。这项建议的目的是在一种新的临床前模型中确定IPSC来源的T细胞的安全性和治疗效果。最重要的假设是，T细胞来源的IPSCs分化为高度活跃的、长寿的抗原特异性T细胞，在没有肿瘤形成和免疫排斥的情况下将介导抗肿瘤免疫。我们将使用三个特定的目标来验证这一假设，以确保：1)T细胞来源的IPSCs在体内没有免疫反应性和致瘤性；2)IPSCs分化为高度狂热的抗原特异性T细胞，可激发针对小鼠肿瘤的抗肿瘤免疫反应；以及3)通过在IPSCs中进行基因组编辑来靶向T细胞抑制途径，将允许生成具有增强抗肿瘤免疫力的T细胞。鉴于ACT对癌症和慢性病毒感染患者是安全有效的， 这项拟议研究的成功完成将为未来利用来自患者特有的IPSCs的免疫细胞进行ACT的开发提供坚实的基础，并最终根除疾病。作为一名学术外科肿瘤学家，我对黑色素瘤有临床和研究兴趣。作为密歇根大学的一名教员，我的临床专业将是治疗晚期黑色素瘤患者，我的研究计划将促进更有效的癌症免疫疗法的开发和应用。细胞与发育生物学系和密歇根大学综合癌症中心拥有世界一流的师资和设施。特别是，我将受益于经验丰富的科学家和临床医生对我的成功所做的深思熟虑、亲力亲为的指导。

 DESCRIPTION (provided by applicant): The incidence of melanoma is increasing worldwide, and the prognosis for patients with advanced or metastatic melanoma remains poor due to limited treatment options. Adoptive cell therapy (ACT) with antigen- specific CD8+ T cells is a promising approach for treating patients with chronic viral infections and a variety of malignancies including melanoma. A major limitation of ACT is poor survival of T cells in vivo following infusion. Less-differentiated T cells with long telomeres are the ideal T-cell subset (termed highly avid T cells) for ACT- based immunotherapy; however, generating large numbers of these "young" T cells is problematic. This limitation can be overcome by using induced pluripotent stem cells (iPSCs) as an unlimited source of T cells against targeted antigens. T cells differentiated from human T cell-derived iPSCs harbor long telomeres and exhibit antigen-specific killing effector functions in vitro. Despite these findings, there is a gap in our knowlede regarding the in vivo safety and therapeutic efficacy of ACT using iPSC-derived T cells. The objective of this proposal is to determine safety and therapeutic efficacy of iPSC-derived T cells in a novel preclinical model. The overarching hypothesis is that T cell-derived iPSCs differentiate into highly avid, long lived antigen- specific T cells that will mediate anti-tumor immunity in the absence of tumor formation and immune rejection. We will test this hypothesis using three specific aims to ensure that: 1) T cell-derived iPSCs display no immunoreactivity and tumorigenicity in vivo; 2) iPSCs differentiate into highly avid antigen-specific T cells that elicit anti-tumor immune response against murine tumors; and 3) targeting T-cell inhibitory pathways by genome editing in iPSCs will allow generation of T cells with enhanced anti-tumor immunity. Given that ACT is safe and effective in patients with cancer and chronic viral infection, successful completion of this proposed study will provide a solid foundation for the future development of ACT using immune cells derived from patient-specific iPSCs and, ultimately, for eradication of disease. As an academic surgical oncologist, I have clinical and research interests in melanoma. As a faculty member at the University of Michigan, my clinical specialty will be treating patients with advanced melanoma and my research program will facilitate the development and application of more effective cancer immunotherapy. The Department of Cell and Developmental Biology and UM Comprehensive Cancer Center have a world-class faculty and facilities. In particular, I will benefit from thoughtful, "hands-on" mentoring by experienced scientists and clinicians who are deeply committed to my success.