Clinical Development of Immunotherapies for Rare Hematologic Maligancies

罕见血液恶性肿瘤免疫疗法的临床开发

• 批准号: 10926402
• 负责人: Nirali Shah
• 金额: $ 88.63万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10926402
• 关键词: Acute Myelocytic Leukemia; Adolescent; Adolescent and Young Adult; Adult; Allogenic; Annual Reports; B-Cell Lymphomas; Biological; Blood; Blood Component Removal; Bone Marrow Transplantation; CAR T cell therapy; Cell Therapy; Cells; Child; Childhood; Clinical; Clinical Protocols; Collaborations; Correlative Study; Data; Development; Disease remission; Dose; Elements; Eligibility Determination; Enrollment; FLT3 gene; Future; Hematologic Neoplasms; Hematology; Heterogeneity; IL3RA gene; Immunotherapeutic agent; Immunotherapy; Infusion procedures; Knowledge; Learning; Marrow; Maximum Tolerated Dose; Myelogenous; Patients; Phase; Phase I/II Trial; Refractory; Relapse; Research; Resources; Role; Stem cell transplant; T-Lymphocyte; Testing; Time; Toxic effect; Translations; Work; Writing; acute myeloid leukemia cell; chemotherapy; chimeric antigen receptor T cells; clinical development; clinical implementation; clinical investigation; design; donor stem cell; experience; first-in-human; improved; improved outcome; insight; international center; leukemia; manufacture; mesothelin; novel; novel therapeutic intervention; participant enrollment; pediatric patients; phase 1 study; phase I trial; programs; relapse prevention; response; safety and feasibility; transplantation therapy; trial design; young adult

Clinical Development of Immunotherapeutic Strategies for Rare Hematologic Malignancies Specific Aim 1: Testing of a first-in-human; first-in-child, CD33 CAR T-cell for AML Based on a CD33 CAR T-cell construct developed in the Fry Lab,42 I led the development of a multi-center, Phase I, CD33 targeted CAR T-cell for children and young adults with relapsed refractory AML. This trial is conducted through the Pediatric Transplantation and Cell Therapy Consortium (PTCTC) with support from the Resource for Clinical Investigation in Blood and Marrow Transplantation (RCI-BMT), the Center for International Blood and Marrow Transplant Research (CIBMTR)/National Marrow Donor Program (NMDP) with cell manufacturing supported by the NCI (NCI-Frederick/BDP). I have led all aspects of the clinical implementation of this study, writing the clinical protocol and coordinating of all elements of IND submission and developing biologic correlative studies. This phase 1/2 trial aims to determine the safety and feasibility of anti-CD33 CAR expressing T-cells in children and adolescents/young adults (AYAs) with relapsed/refractory AML. Phase 1 will determine the maximum tolerated dose of CD33 CAR T-cell cells using a 3+3 trial design. Phase 2 is an expansion phase designed to evaluate the rate of response to CD33 CAR T-cells. Secondary objectives for all subjects include: 1) To determine the feasibility of manufacturing CD33 CAR T-cells from subjects with AML and 2) To determine the feasibility of infusing CD33 CAR T-cells in subjects with AML. Given the concerns for heterogeneity of CD33 expression in AML, compounded by concerns for myeloid directed toxicity of normal CD33 targeting, this trial is built to serve as a bridge to allogeneic HSCT with the dual purposes of prevention of relapse and salvage from aplasia, should that be a concern. Exploratory objectives will be performed collaboratively and include a host of biologic correlatives, including CAR T-cell expansion and persistence, CD33 expression and toxicity profiling. Enrollment is ongoing. Knowledge gained has included learning the best approach to get a patient with relapsed/refractory AML to CAR T-cell therapy and how to effectively bridge them to both apheresis and the actual CAR T-cell infusion. Importantly, a CAR T-cell product has been successfully manufactured for all patients enrolled on study, which is particularly remarkable as this has been a particular challenge for patients with AML. Future directions include exploration of biologic correlatives and incorporation of allogeneic (donor-derived) T-cells for the starting material for patients with post-HSCT relapse to improve CAR T-cell functionality and manipulating the design of the CAR construct. As of the time of this annual report, we have completed the dose-escalation phase of the study and are in the expansion phase. We are now exploring the biologic correlatives relevant to this trial Specific Aim 2: Translation of novel CAR T-cells in AML Given the ongoing clinical need for development of CAR T-cells in AML, our future endeavors will be focused on further exploring novel CAR T-cells in AML. Based on the early work emerging from our CD33 CAR T-cell trial, we anticipate that biologic correlative will be informative to helping us to understand what elements may lead to improved outcomes for CAR T-cell therapies in AML. Anticipated future efforts include development of 3 phase I studies for patients with relapsed/refractory AML; targeting FLT3 CAR (developed at the NCI), CD123 CAR, and mesothelin (in collaboration with Dr. Raffit Hassan). We anticipate that our pipeline and portfolio over the next several years will provide critical insights into improving outcomes of AML CAR T-cell therapy.

罕见血液恶性肿瘤免疫治疗策略的临床开发具体目标 1：首次人体测试；首个用于治疗 AML 的儿童 CD33 CAR T 细胞 基于 Fry 实验室开发的 CD33 CAR T 细胞结构，42 我领导了针对儿童的多中心、I 期 CD33 靶向 CAR T 细胞的开发以及患有复发性难治性 AML 的年轻人。该试验是通过儿科移植和细胞治疗联盟 (PTCTC) 在血液和骨髓移植临床研究资源 (RCI-BMT)、国际血液和骨髓移植研究中心 (CIBMTR)/国家骨髓捐赠者的支持下进行的由 NCI (NCI-Frederick/BDP) 支持的细胞制造计划 (NMDP)。我领导了这项研究临床实施的各个方面，编写临床方案并协调 IND 提交的所有要素并开展生物学相关研究。这项 1/2 期试验旨在确定表达抗 CD33 CAR 的 T 细胞在患有复发/难治性 AML 的儿童和青少年/年轻人 (AYAs) 中的安全性和可行性。第一阶段将使用 3+3 试验设计确定 CD33 CAR T 细胞的最大耐受剂量。第 2 阶段是扩展阶段，旨在评估 CD33 CAR T 细胞的反应率。所有受试者的次要目标包括：1) 确定从 AML 受试者中制造 CD33 CAR T 细胞的可行性；2) 确定将 CD33 CAR T 细胞输注到 AML 受试者中的可行性。考虑到对 AML 中 CD33 表达异质性的担忧，再加上对正常 CD33 靶向的骨髓定向毒性的担忧，该试验旨在作为同种异体 HSCT 的桥梁，其双重目的是预防复发和挽救发育不全，如果成为一个问题。探索性目标将通过合作执行，包括许多生物相关性，包括 CAR T 细胞扩增和持久性、CD33 表达和毒性分析。报名正在进行中。获得的知识包括学习让复发/难治性 AML 患者接受 CAR T 细胞治疗的最佳方法，以及如何有效地将其与血浆分离术和实际的 CAR T 细胞输注联系起来。重要的是，CAR T 细胞产品已成功为所有参与研究的患者生产，这一点尤其引人注目，因为这对 AML 患者来说是一个特殊的挑战。未来的方向包括探索生物相关性以及将同种异体（供体来源的）T 细胞纳入 HSCT 后复发患者的起始材料，以改善 CAR T 细胞功能并操纵 CAR 构建体的设计。截至本年度报告发布时，我们已经完成了研究的剂量递增阶段，并处于扩展阶段。我们现在正在探索与本试验相关的生物学相关性 具体目标 2：新型 CAR T 细胞在 AML 中的转化 鉴于对 AML 中 CAR T 细胞开发的持续临床需求，我们未来的努力将集中于进一步探索新型 CAR AML 中的 T 细胞。根据我们的 CD33 CAR T 细胞试验的早期工作，我们预计生物相关性将提供信息，帮助我们了解哪些因素可能导致 AML CAR T 细胞疗法的结果改善。预计未来的工作包括针对复发/难治性 AML 患者开展 3 项 I 期研究；靶向 FLT3 CAR（在 NCI 开发）、CD123 CAR 和间皮素（与 Raffit Hassan 博士合作）。我们预计未来几年我们的产品线和产品组合将为改善 AML CAR T 细胞治疗的结果提供重要的见解。