Adoptive Cell Therapy with Rejuvenated Antigen-specific T Cells

使用复兴的抗原特异性 T 细胞进行过继细胞疗法

• 批准号: 8950232
• 负责人: Fumito Ito
• 金额: $ 4.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-25 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8950232
• 关键词: Address; Animal Model; Antigen Targeting; Antigens; Autologous; CD8B1 gene; Cell Therapy; Cells; Chronic; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Comprehensive Cancer Center; Development; Developmental Cell Biology; Disease; Ensure; Eukaryotic Cell; Exhibits; Faculty; Foundations; Future; Gene Rearrangement; Generations; Genome engineering; Goals; Grant; Health; Human; Immune; Immune response; Immunology; Immunotherapy; In Vitro; Incidence; Individual; Infusion procedures; Knock-in Mouse; Knowledge; Life; Malignant Neoplasms; Mediating; Mentors; Metastatic Melanoma; Michigan; Mus; Mutation; Pathway interactions; Patients; Pattern; Pre-Clinical Model; Proteins; Protocols documentation; Reporter; Research; Risk; Safety; Scientist; Solid; Source; Surgical Oncologist; System; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Training; Treatment Efficacy; Tumor Immunity; Tumorigenicity; Universities; Virus; Virus Diseases; Work; base; cancer immunotherapy; cancer therapy; experience; gene function; gene therapy; genome editing; immunogenicity; immunoreactivity; in vivo; induced pluripotent stem cell; insight; interest; killings; medical specialties; melanoma; member; novel; outcome forecast; personalized cancer therapy; pluripotency; prevent; programs; self-renewal; skills; success; telomere; tumor; tumor immunology

 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.

 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。使用抗原特异性CD 8 + T细胞的免疫细胞疗法（ACT）是用于治疗患有慢性病毒感染和多种恶性肿瘤（包括黑色素瘤）的患者的有前景的方法。ACT的主要限制是输注后T细胞在体内的存活率差。具有长端粒的分化程度较低的T细胞是基于ACT的免疫疗法的理想T细胞亚群（称为高亲和力T细胞）;然而，产生大量这些“年轻”T细胞是有问题的。 这种限制可以通过使用诱导多能干细胞（iPSC）作为针对靶抗原的T细胞的无限来源来克服。从人T细胞衍生的iPSC分化的T细胞具有长端粒并在体外表现出抗原特异性杀伤效应子功能。尽管有这些发现，但我们对使用iPSC衍生的T细胞的ACT的体内安全性和治疗功效的了解存在差距。该提案的目的是确定iPSC衍生的T细胞在新型临床前模型中的安全性和治疗功效。 首要假设是T细胞衍生的iPSC分化成高度亲合力的、长寿命的抗原特异性T细胞，其将在不存在肿瘤形成和免疫排斥的情况下介导抗肿瘤免疫。我们将使用三个具体目标来测试这一假设，以确保：1）T细胞衍生的iPSC在体内不显示免疫反应性和致瘤性; 2）iPSC分化成引发针对鼠肿瘤的抗肿瘤免疫应答的高度亲合力的抗原特异性T细胞;以及3）通过iPSC中的基因组编辑靶向T细胞抑制途径将允许产生具有增强的抗肿瘤免疫力的T细胞。鉴于ACT对癌症和慢性病毒感染患者安全有效， 这项研究的成功完成将为未来使用源自患者特异性iPSC的免疫细胞开发ACT并最终根除疾病提供坚实的基础。 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。细胞和发育生物学系和UM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的深思熟虑的“动手”指导，他们深深致力于我的成功。