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（由适用提供）：全球黑色素瘤的事件正在增加，由于治疗选择有限，患有晚期或转移性黑色素瘤患者的预后仍然很差。具有抗原特异性CD8+ T细胞的过养细胞疗法（ACT）是治疗慢性病毒感染患者和包括黑色素瘤在内的各种恶性肿瘤的一种有前途的方法。 ACT的主要局限性是输注后T细胞在体内的存活不良。对于基于ACT的免疫疗法的理想T细胞子集（称为高度狂热的T细胞），具有长端粒的T细胞是理想的T细胞子集（称为高度狂热的T细胞）。但是，产生大量“年轻” T细胞是有问题的。可以通过使用诱导的多能干细胞（IPSC）作为针对靶向抗原的T细胞的无限来源来克服这种局限性。与人T细胞衍生的IPSC区分开的T细胞具有长长的端粒，并在体外杀死了特定的杀伤效应子功能。尽管有这些发现，但我们的知识方面存在差距，即使用IPSC衍生的T细胞具有ACT的体内安全性和治疗有效性。该建议的目的是确定新型临床前模型中IPSC衍生的T细胞的安全性和治疗有效性。总体假设是，T细胞衍生的IPSC分化为高度狂热，长期存在的抗原特异性T细胞，在没有肿瘤形成和免疫反应的情况下将中值抗肿瘤免疫成员。我们将使用三个特定目的来检验这一假设，以确保：1）T细胞衍生的IPSC在体内没有免疫反应性和肿瘤性； 2）IPSC分化为高度狂热的抗原特异性T细胞，从而引起针对鼠肿瘤的抗肿瘤免疫激素； 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抗肿瘤免疫组织化学的T细胞。鉴于该行为对于癌症和慢性病毒感染的患者是安全有效的， 这项拟议的研究的成功完成将为ACT的未来发展提供稳固的基础，该免疫细胞使用源自患者特异性IPSC的免疫细胞，并最终用于疾病的放射分配。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。作为密歇根大学的教职员工，我的临床专长将治疗患有晚期黑色素瘤的患者，而我的研究计划将支持开发和应用更有效的癌症免疫疗法。细胞和发育生物学系和UM综合癌症中心拥有世界一流的教职员工和设施。特别是，我将受益于经验丰富的科学家和临床医生，他们深深致力于我的成功。