13 Stem Cell Transplantation and Cellular Therapy

项目摘要/摘要 干细胞移植和细胞治疗(SCTCT)计划侧重于造血干细胞 移植(HSCT)、细胞介导的免疫疗法以及干细胞和间充质干细胞疗法 基质细胞(MSCs)。该计划有来自25个部门的80名成员(38名初级成员，40名副成员，2名附属成员)。 该项目的负责人是理查德·钱普林博士，他是一位经验丰富的临床和翻译研究员，并与 领军者是细胞治疗专家Katayoun Rezvani博士和干细胞领军人物Elizabeth Shpall博士 细胞、脐带血移植和再生医学。该计划的目标是推进和优化 利用造血干细胞移植和细胞治疗通过转译研究桥接干细胞治疗癌症 生物学、造血学、移植/肿瘤免疫学和再生医学。该计划有4个具体的 目标涉及四个主题：目标1)改善造血移植的临床结果；目标2) 改善支持性护理，特别是预防感染和移植物抗宿主疾病，并防止 细胞免疫治疗中出现的细胞因子释放综合征；目标3)开发有效的细胞 涉及抗原特异性T细胞和NK细胞的免疫治疗；以及目的4)确定基本的生物机制 对正常和恶性干细胞进行研究，并开发干细胞和以间充质干细胞为基础的组织再生疗法。 年度直接同行审查资金总额为990万美元，其中240万美元(24%)来自NCI赠款，包括1个P01和 1 U01。自上次竞争性续签以来，年度直接同行审查资金总额增加了19%。国防部 安德森维持着全国最大的造血移植计划。自上次提交以来， 该计划发表了726篇文章：381篇(52%)代表计划内协作，304篇(42%) 代表方案间协作，444个(61%)包括外部协作。出版物有 出现在影响较大的期刊上，包括N Engl J Med和J Clin Invest。41%的出版物 已在IF&>；5期刊上发表过，15%已在IF&>；10期刊上发表过。计划成员有 利用了所有14个共享资源。成就包括开发单倍体匹配的新方法和 脐带血移植；建立来特莫韦预防HSCT后CMV感染的疗效；开发 符合GMP的NK细胞体外扩增系统及其产生嵌合抗原受体(CAR)NK 增强抗肿瘤细胞毒性的细胞，并将其纳入I/II期临床试验；开发新的 制造汽车T细胞的技术；领导多中心研究，导致FDA批准阿昔卡班 Ciloucel CAR T细胞治疗淋巴瘤；识别新的免疫治疗靶抗原； 针对异常表达的白血病抗原的新型单抗和CAR T细胞的研制 PR1；内源性抗肿瘤T细胞的选择和扩增；以及证明体外岩藻糖化 加速脐带血移植的植入。这些成就是概念的延伸和 由项目研究人员进行的临床前研究。

PROJECT SUMMARY/ABSTRACT The Stem Cell Transplantation and Cellular Therapy (SCTCT) Program focuses on hematopoietic stem cell transplantation (HSCT), cell-mediated immune therapy, and therapy involving stem cells and mesenchymal stromal cells (MSCs). The program has 80 members (38 primary, 40 associate, 2 adjunct) from 25 departments. The program leader is Dr. Richard Champlin, an accomplished clinical and translational investigator, and co- leaders are Dr. Katayoun Rezvani, an expert in cellular therapy, and Dr. Elizabeth Shpall, a leader in stem cells, cord blood transplantation, and regenerative medicine. The program's goal is to advance and optimize the use of HSCT and cellular therapy for treatment of cancer through translational research bridging stem cell biology, hematopoiesis, transplant/tumor immunology, and regenerative medicine. The program has 4 specific aims that address 4 themes: Aim 1) to improve the clinical outcomes of hematopoietic transplantation; Aim 2) to improve supportive care, particularly to prevent infections and graft-vs-host disease, and also to prevent cytokine release syndrome seen with cellular immune therapy; Aim 3) to develop effective cellular immunotherapy involving antigen-specific T cells and NK cells; and Aim 4) to define basic biologic mechanisms of normal and malignant stem cells and to develop stem cell and MSC-based therapies for tissue regeneration. Annual direct peer-reviewed funding totals $9.9M, of which $2.4M (24%) is from NCI grants, including 1 P01 and 1 U01. Since the last competitive renewal, total annual direct peer-reviewed funding has increased by 19%. MD Anderson maintains the largest hematopoietic transplantation program in the nation. Since the last submission, the program has published 726 articles: 381 (52%) represent intra-programmatic collaborations, 304 (42%) represent inter-programmatic collaborations, and 444 (61%) include external collaborations. Publications have appeared in high-impact journals including N Engl J Med and J Clin Invest. Forty-one percent of publications have appeared in journals with IF >5, and 15% have been in journals with IF >10. Program members have utilized all 14 Shared Resources. Achievements include developing novel approaches for haploidentical and cord blood transplants; establishing the efficacy of letermovir to prevent CMV infections after HSCT; developing a GMP-compliant ex vivo expansion system for NK cells and producing chimeric antigen receptor (CAR) NK cells, which augment antitumor cytotoxicity, and taking these into phase I/II clinical trials; development of novel technology for manufacturing CAR T cells; leading the multicenter study leading to FDA approval of axicabtagene ciloleucel CAR T cell therapy for lymphoma; identification of novel target antigens for immunotherapy; development of a novel monoclonal antibody and CAR T cell that targets aberrantly expressed leukemia antigen PR1; selection and expansion of endogenous antitumor T cells; and demonstration that ex vivo fucosylation accelerates engraftment of cord blood transplants. These accomplishments are extensions of concepts and preclinical studies by program investigators.