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

候选人：埃里克·史密斯，医学博士，斯隆纪念医院骨髓瘤服务助理 凯特琳癌症中心，以及他推荐的K08导师、医学博士雷尼尔·布伦特延斯的实验室里的博士后。在……里面 在布伦特金斯实验室，史密斯博士开发了优化的完全人类嵌合抗原受体(CAR)载体，用于 多发性骨髓瘤的治疗。B细胞成熟抗原(BCMA)靶向CAR T细胞来源 他的工作正在四个单独的临床试验中进行临床评估，其中包括一个多机构的I/II阶段 注册研究。G蛋白偶联受体C5D(GPRC5D；他验证了一种新的靶点 MM的免疫疗法)他开发的靶向CAR T细胞计划于年进入临床研究 2018年12月。虽然BCMA靶向CAR T细胞治疗的应答率很高，但许多患者继续 旧病复发。史密斯博士建议研究CAR T细胞复发的机制，重点放在 MM肿瘤微环境(TME)可能导致次优反应，并评估新的CAR载体 以增强CAR T细胞的效能。在进行这项研究的过程中，他计划获得 以及成功过渡到独立实验室调查员所需的智力技能和经验。 职业发展计划：史密斯博士有一个基于导师关系的详细职业发展计划，以及 顾问委员会、合作者和精选课程工作。他的主要导师布伦特延斯博士将继续 提供与CAR T细胞治疗和T细胞生物学相关的培训和发展。他的顾问委员会 拥有互补的专业知识，这将加强他的培训和发展。所有顾问都有广泛的 先进的老鼠癌症模型方面的专业知识。Wolchok博士是T细胞免疫学专家；温德尔博士 在CRISPR方面有丰富的经验；Abdul-Wahab博士是血液系统恶性肿瘤遗传学的领导者， 包括基因表达分析；Dhodapkar博士的职业生涯是研究MM 微环境。更多的非正式互动和正式课程作业将有助于史密斯博士 上述领域的发展以及细胞周期数据分析和生物统计。助学金写作，演讲， 在整个赠款期间，领导技能将得到加强。这些经历将导致 建立一个独立的实验室小组，专注于过继细胞治疗和R01应用。 研究计划：在目标1中，史密斯博士将通过比较多个 BCMA/GPRC5D双靶向CAR T细胞策略在抗原逃逸模型中的应用 双目的方法。目的2，着重于了解人类背景下的抗原阳性复发 MM TME通过使用多重转基因人源化MISTRG6小鼠模型 MM细胞和相关的骨髓免疫细胞，以及通过对来自 接受CAR T细胞治疗的患者。他将评估可能克服MM TME的合理装甲车方法 免疫抑制，以提高晚期MM对CAR T细胞治疗反应的持久性。

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.