Novel Immunotherapeutic Approaches and Tools Utilizing Allogeneic T Cells

利用同种异体 T 细胞的新型免疫治疗方法和工具

• 批准号: 7660704
• 负责人: HEATHER Jill SYMONS
• 金额: $ 17.75万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660704
• 关键词: Acute; Adoptive Immunotherapy; Alloantigen; Allogeneic Lymphocyte; Allogenic; Antigens; Biological Assay; Cells; Clinical; Clinical Trials; Commit; Cyclophosphamide; Cytomegalovirus; Data; Disease-Free Survival; Dose; Engraftment; Environment; Frequencies; Generations; Genotype; Goals; Gold; Graft Rejection; HLA Antigens; Hematologic Neoplasms; Immune; Immunity; Immunology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Incidence; Infection; Infusion procedures; Laboratories; Light; Major Histocompatibility Complex; Mature T-Lymphocyte; Mediating; Mentors; Methods; Natural Killer Cells; Opportunistic Infections; Outcome; Patients; Phase; Phase II Clinical Trials; Principal Investigator; Proliferating; Prophylactic treatment; Relapse; Research; Research Personnel; Rest; Safety; Seasons; Series; Stem cell transplant; T-Lymphocyte; Thymus Gland; Toxic effect; Transplantation; Treatment Protocols; Viral; base; career; chronic graft versus host disease; conditioning; design; graft vs host disease; improved; in vivo; killer immunoglobulin-like receptor; mortality; novel; preclinical study; reconstitution; response; tool; tumor

DESCRIPTION (provided by applicant): Allergenic stem cell transplantation (alloSCT) is a well-established therapy for hematologic malignancies. Despite its curative potential, alloSCT is limited by the lack of human leukocyte antigen (HLA)-matched donors for most patients and by significant toxicity, especially GVHD and opportunistic infection. We have used high dose, post-transplantation cyclophosphamide (Cy) in two existing clinical trials to enable partially HLA-mismatched alloSCT after nonmyeloablative conditioning and to eliminate the requirement for prolonged pharmacologic immunosuppression after HLA-matched alloSCT. Both of these trials have shown remarkably low incidences of acute and chronic GVHD, a low incidence of serious opportunistic infection, and low treatment-related mortality. The central objectives of this proposal are to characterize the effects of high-dose, post-transplantation Cy on alloreactivity and immune reconstitution after alloSCT, and to use high-dose, post-transplantation Cy to suppress graft rejection and graft-versus-host disease (GVHD) after lethal conditioning and partially HLA-mismatched alloSCT. Our studies are based on the hypothesis that post-transplantation Cy selectively induces tolerance in proliferating, alloreactive T cells while sparing resting T cells responsible for immunity to infection; i.e. post-transplantation Cy induces selective in vivo allodepletion. Accordingly, we propose the following specific aims: (1) Characterize the mechanism(s) of post-transplantation Cy-induced tolerance, (2) Characterize the effects of post-transplantation Cy on the reconstitution of T cells and antigen-specific T cells, and (3) Conduct a phase II trial of myeloablative, haploidentical BMT with T cell replete grafts and post-transplantation Cy. The overall career goal of the candidate is to become an independent translational investigator in clinical immunotherapy. Immediate career goals are to (1) develop expertise in immunology based laboratory assays and (2) develop expertise in the design and conduct of a clinical trial to treat patients with advanced hematologic malignancies. A mentoring committee comprising seasoned investigators will guide the candidate through a series of phased research endeavors in a rich, academic environment strongly committed to the candidate.

描述（由申请方提供）：过敏性干细胞移植（alloSCT）是一种成熟的血液恶性肿瘤治疗方法。尽管具有治疗潜力，但alloSCT受到大多数患者缺乏人类白细胞抗原（HLA）匹配供体以及严重毒性（特别是GVHD和机会性感染）的限制。我们已经在两项现有的临床试验中使用了高剂量的移植后环磷酰胺（Cy），以使非清髓性预处理后部分HLA不匹配的alloSCT，并消除HLA匹配的alloSCT后长期药物免疫抑制的要求。这两项试验均显示急性和慢性GVHD的发生率非常低，严重机会性感染的发生率低，治疗相关死亡率低。该提案的中心目标是表征高剂量的移植后Cy对alloSCT后同种异体反应性和免疫重建的影响，并使用高剂量的移植后Cy抑制致死性条件和部分HLA错配的alloSCT后的移植物排斥反应和移植物抗宿主病（GVHD）。我们的研究是基于这样的假设，即移植后Cy选择性地诱导增殖的同种异体反应性T细胞的耐受性，同时保留负责对感染的免疫的静息T细胞;即移植后Cy诱导选择性体内同种异体耗竭。因此，我们提出了以下具体目标：（1）表征移植后Cy诱导的耐受的机制，（2）表征移植后Cy对T细胞和抗原特异性T细胞的重建的作用，和（3）进行清髓性、单倍体相合BMT与T细胞充满的移植物和移植后Cy的II期试验。候选人的总体职业目标是成为临床免疫治疗的独立翻译研究者。近期职业目标是（1）发展免疫学实验室检测的专业知识，（2）发展临床试验设计和实施的专业知识，以治疗晚期恶性血液病患者。一个由经验丰富的调查人员组成的指导委员会将指导候选人在一个丰富的学术环境中进行一系列分阶段的研究工作。