Understanding and addressing sub-optimal responses to CAR T cell therapy for Multiple Myeloma

了解和解决多发性骨髓瘤 CAR T 细胞疗法的次优反应

• 批准号: 9977984
• 负责人: Eric L Smith
• 金额: $ 25.27万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977984
• 关键词: Address; Adoptive Cell Transfers; Advisory Committees; Antigen Targeting; Antigens; Area; Autologous; B cell therapy; B-Lymphocytes; Biometry; Bone Marrow; CAR T cell therapy; CD19 gene; Cancer Model; Cell Culture Techniques; Cell Maturation; Cell physiology; Cells; Cellular biology; Clinic; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Committee Members; Data; Data Analyses; Development; Development Plans; Disease; Disease remission; Doctor of Philosophy; Dose; Down-Regulation; Engineering; Engraftment; Focus Groups; Future; G-Protein-Coupled Receptors; Gene Expression Profiling; Genes; Genetic; Grant; Hematologic Neoplasms; Human; Immune; Immunology; Immunosuppression; Immunotherapy; In Vitro; In complete remission; Institution; Institutional Review Boards; Interleukin-12; Investigation; Laboratories; Lead; Leadership; Marrow; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Modality; Modeling; Multiple Myeloma; Mus; Patients; Phase; Population; Postdoctoral Fellow; Refractory; Relapse; Reporting; Research; Research Personnel; Sampling; Schedule; Secondary to; Services; T cell therapy; T-Lymphocyte; TNFRSF17 gene; TNFSF5 gene; Testing; Therapeutic; Therapy trial; Toxic effect; Training; Transgenic Organisms; Tumor Immunity; Work; Writing; Xenograft Model; base; career; career development; chimeric antigen receptor; chimeric antigen receptor T cells; clinical investigation; clinical translation; cohort; design; design and construction; experience; first-in-human; genetic manipulation; humanized mouse; improved; in vivo; infancy; lead optimization; mouse model; next generation; novel; novel therapeutics; phase 1 study; prevent; research clinical testing; response; skills; stem cells; targeted treatment; tumor; tumor microenvironment; tumor-immune system interactions; vector

Candidate: Eric Smith, MD PhD, is an Assistant Attending on the Myeloma Service at Memorial Sloan Kettering Cancer Center, and a post-doc in the lab of his proposed K08 mentor, Renier Brentjens, MD PhD. In the Brentjens lab, Dr. Smith developed optimized fully human chimeric antigen receptor (CAR) vectors for the treatment of multiple myeloma (MM). B cell maturation antigen (BCMA) targeted CAR T cells stemming from his work are under clinical evaluation in four separate clinical trials, including a multi-institution phase I/II registration study. G-protein-coupled receptor C5D (GPRC5D; a novel target he validated for the immunotherapy of MM) targeted CAR T cells he developed are scheduled to enter clinical investigation in 12/2018. While response rates to BCMA targeted CAR T cell therapy are high, many patients go on to relapse. Dr. Smith proposes to study mechanisms of CAR T cell relapse, with a focus on interactions in the MM tumor microenvironment (TME) that may lead to sub-optimal responses, and evaluate novel CAR vectors to enhance CAR T cell efficacy. In the course of carrying out this research, he plans to acquire the technical and intellectual skills and experience required to transition successfully to independent laboratory investigator. Career Development Plan: Dr. Smith has a detailed career development plan based on mentorship, an advisory committee, collaborators, and select course work. Dr. Brentjens, his primary mentor, will continue to provide training and development relating to CAR T cell therapy and T cell biology. His advisory committee has complementary expertise that will enhance his training and development. All advisors have extensive expertise on advanced mouse models of cancer. Dr. Wolchok is an expert on T cell immunology; Dr. Wendel has significant experience with CRISPR; Dr. Abdul-Wahab is a leader in genetics of hematologic malignancies, including gene expression analyses; and Dr. Dhodapkar has spent his career studying the MM microenvironment. Additional informal interactions and formal course work will contribute to Dr. Smith's development in the above areas as well as CyTOF data analysis and biostatistics. Grant writing, presentation, and leadership skills will be enhanced throughout the grant period. These experiences will lead to the establishment of an independent lab group focused on adoptive cellular therapy and an R01 application. Research Plan: In aim 1, Dr. Smith will address target antigen loss mediated relapse by comparing multiple BCMA/GPRC5D dual-targeted CAR T cell strategies in a model of antigen escape to determine an optimal dual-targeting approach. Aim 2, focuses on understanding antigen positive relapse in the setting of the human MM TME through use of the multiply-transgenic humanized MISTRG6 murine model that uniquely supports MM cells and associated bone marrow immune cells, as well as through the study of marrow samples from CAR T cell treated patients. He will assess rational armored CAR approaches that may overcome MM TME immune suppression in order to enhance the durability of response to CAR T cell therapy in advanced MM.

候选人：埃里克史密斯，医学博士，是一个助理出席骨髓瘤服务在纪念斯隆 Kettering癌症中心，以及他的K 08导师Renier Brentjens，MD PhD实验室的博士后。在 在Brentjens实验室，Smith博士开发了优化的全人嵌合抗原受体（CAR）载体，用于 治疗多发性骨髓瘤（MM）。B细胞成熟抗原（BCMA）靶向的CAR T细胞来源于 他的工作正在四个独立的临床试验中进行临床评估，包括一个多机构I/II期 注册研究。G蛋白偶联受体C5 D（GPRC 5D;一种新的靶点，他验证了 他开发的MM免疫疗法）靶向CAR T细胞计划进入临床研究， 12/2018.虽然对BCMA靶向CAR T细胞疗法的应答率很高，但许多患者继续进行治疗。 复发史密斯博士建议研究CAR T细胞复发的机制，重点是在细胞周期中的相互作用。 MM肿瘤微环境（TME）可能导致次优反应，并评估新型CAR载体 以增强CAR T细胞的功效。在进行这项研究的过程中，他计划获得技术 以及成功过渡到独立实验室研究者所需的知识技能和经验。 职业发展计划：史密斯博士有一个详细的职业发展计划， 咨询委员会，合作者，并选择课程工作。他的主要导师布伦特延斯博士将继续 提供与CAR T细胞疗法和T细胞生物学相关的培训和发展。他的顾问委员会 有互补的专业知识，将加强他的培训和发展。所有顾问都有广泛的 先进的癌症小鼠模型的专业知识。Wolchok博士是T细胞免疫学专家; Wendel博士 Abdul-Wahab博士是血液恶性肿瘤遗传学的领导者， 包括基因表达分析; Dhodapkar博士的职业生涯一直在研究MM 微环境额外的非正式互动和正式的课程工作将有助于史密斯博士的 在上述领域的发展以及CyTOF数据分析和生物统计学。写作，演讲， 在整个资助期内，我们会加强学生的领导才能。这些经验将导致 成立了一个独立的实验室小组，专注于过继细胞治疗和R 01应用。 研究计划：在目标1中，Smith博士将通过比较多个靶抗原缺失介导的复发， BCMA/GPRC 5D双靶向CAR T细胞策略在抗原逃逸模型中的应用，以确定 双重目标方法。目的2，着重于了解抗原阳性复发的背景下， 通过使用多转基因人源化MISTRG 6鼠模型， MM细胞和相关的骨髓免疫细胞，以及通过研究来自 CAR T细胞治疗的患者。他将评估可能克服MM TME的合理装甲CAR方法 免疫抑制，以增强对晚期MM中CAR T细胞疗法的应答的持久性。