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

基本信息

批准号：
9319670
负责人：
Fumito Ito
金额：
$ 17.5万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-25 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319670
关键词：
Address Adoptive Transfer Animal Model Antigen Targeting Antigens Autologous CD8-Positive T-Lymphocytes Cell Differentiation process Cell Therapy Cells Chronic Clinical Clinical Research Clone Cells Clustered Regularly Interspaced Short Palindromic Repeats Comprehensive Cancer Center Development Developmental Biology Disease Ensure Eukaryotic Cell Exhibits Faculty Foundations Future Gene Rearrangement Generations Genome engineering Goals Grant Human Immune Immune response Immunology Immunotherapy In Vitro Incidence Individual Infusion procedures Knock-in Knowledge 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 cell differentiation T-Cell Receptor Genes T-Lymphocyte T-Lymphocyte Subsets Technology Testing Therapeutic Training Treatment Efficacy Tumor Immunity Tumorigenicity Universities Virus Virus Diseases Whole Organism Work 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 public health relevance self renewing cell skills success telomere tumor tumor immunology

项目摘要

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世界范围内不断增加，并且由于治疗选择有限，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 CD8+ T 细胞的过继细胞疗法 (ACT) 是一种有前景的方法。用于治疗患有慢性病毒感染和包括黑色素瘤在内的多种恶性肿瘤的患者，ACT 的一个主要限制是输注后 T 细胞在体内的存活率较低。基于 ACT 的免疫疗法的理想 T 细胞亚群（称为高度活跃的 T 细胞）；然而，生成大量这些“年轻”T 细胞是有问题的，可以通过使用诱导多能干细胞 (iPSC) 来克服。源自人类 T 细胞的 iPSC 分化而来的 T 细胞具有无限的来源，并具有长端粒并在体外表现出抗原特异性杀伤效应功能。使用 iPSC 衍生的 T 细胞进行 ACT 的体内安全性和治疗功效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。总体假设是 T 细胞衍生的 iPSC 会分化。转化为高度活跃、寿命长的抗原特异性 T 细胞，这些 T 细胞将在没有肿瘤形成和免疫排斥的情况下介导抗肿瘤免疫。我们将使用三个特定目标来检验这一假设，以确保：1) T 细胞衍生的 iPSC 不表现出任何变化。体内免疫反应性和致瘤性；2）iPSC 分化为高度活跃的抗原特异性 T 细胞，引发针对小鼠肿瘤的抗肿瘤免疫反应；3）通过 iPSC 中的基因组编辑靶向 T 细胞抑制途径将允许生成具有增强抗肿瘤免疫力鉴于 ACT 对于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患者特异性 iPSC 衍生的免疫细胞开发 ACT 奠定坚实的基础，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，我的研究项目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一个。特别是，我将受益于经验丰富的科学家和参议员的周到、“实践”指导，他们致力于我的成功。