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

基本信息

批准号：
10676215
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
项目类别：
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/10676215
关键词：
Address Adoptive Cell Transfers Advisory Committees Antigen Targeting Antigens Area Autologous B cell therapy B-Cell Acute Lymphoblastic Leukemia 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 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 Infusion procedures 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 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 manufacture mouse model next generation novel novel therapeutic intervention novel therapeutics patient derived xenograft model phase 1 study prevent research clinical testing response skills stem cells targeted treatment tumor tumor microenvironment tumor-immune system interactions vector

项目摘要

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（Eric Smith），医学博士学位，是纪念斯隆（Memorial Sloan）骨髓瘤服务的助理 Kettering Cancer Center，以及他拟议的K08导师Renier Brentjens，医学博士的实验室的大约一名。在 Brentjens实验室Smith博士开发了优化的完全人类嵌合抗原受体（CAR）向量多发性骨髓瘤（MM）的治疗。 B细胞成熟抗原（BCMA）靶向的CAR T细胞他的工作在四个独立的临床试验中进行了临床评估，包括多机构的I/II阶段注册研究。 G蛋白偶联受体C5D（GPRC5D；他为他验证的新目标他开发的靶向汽车T细胞的免疫疗法计划在 12/2018。虽然对BCMA靶向CAR T细胞疗法的反应率很高，但许多患者继续进行复发。史密斯博士建议研究汽车T细胞复发的机制，重点是 MM肿瘤微环境（TME），可能导致亚最佳反应，并评估新型的CAR矢量增强汽车T细胞功效。在进行这项研究的过程中，他计划获得技术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：史密斯博士根据指导制定了详细的职业发展计划咨询委员会，合作者和选择课程工作。他的主要导师Brentjens博士将继续提供与CAR T细胞疗法和T细胞生物学有关的培训和开发。他的咨询委员会具有互补的专业知识，可以增强他的培训和发展。所有顾问都有广泛的高级小鼠癌模型的专业知识。 Wolchok博士是T细胞免疫学专家；温德尔博士在CRISPR方面具有丰富的经验； 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博士的职业生涯都在研究MM 微环境。其他非正式互动和正式课程工作将为史密斯博士的上述领域的发展以及数据分析和生物统计学。授予写作，演示文稿，在整个赠款期间，领导技能将得到提高。这些经历将导致建立一个专注于收养细胞疗法和R01应用的独立实验室组。研究计划：在AIM 1中，史密斯博士将通过比较多个来解决目标抗原损失介导的复发 BCMA/GPRC5D抗原逃生模型中的双重靶向汽车T细胞策略以确定最佳双目标方法。目标2，专注于理解人类环境中的抗原阳性复发 MM TME通过使用唯一支持的多重转基因人道化mistrg6鼠模型 MM细胞和相关的骨髓免疫细胞，以及通过研究骨髓样品 CAR T细胞治疗患者。他将评估可能克服MM TME的理性装甲车方法免疫抑制以提高晚期MM中对CAR T细胞疗法的反应持续性。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

GPRC5D-Targeted CAR T Cells for Myeloma.

DOI：
10.1056/nejmoa2209900
发表时间：
2022-09-29
期刊：
The New England journal of medicine
影响因子：
0
作者：
通讯作者：

The Future of Chimeric Antigen Receptor T Cell Therapy.

嵌合抗原受体 T 细胞疗法的未来。

DOI：
10.1016/j.hoc.2023.06.005
发表时间：
2023
期刊：
Hematology/oncology clinics of North America
影响因子：
0
作者：
Smith,EricL
通讯作者：
Smith,EricL

Finding the optimal partner to pair with bispecific antibody therapy for multiple myeloma.

DOI：
10.1158/2643-3230.bcd-21-0073
发表时间：
2021-07
期刊：
Blood cancer discovery
影响因子：
11.2
作者：
Louvet C;Nadeem O;Smith EL
通讯作者：
Smith EL

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Eric L Smith其他文献

Revision Total Knee Arthroplasty in an Outpatient Setting: A Growing Alternative.

门诊全膝关节翻修术：一种不断增长的替代方案。

DOI：
发表时间：
2024
期刊：
Journal of Arthroplasty
影响因子：
3.5
作者：
Darren Z. Nin;Ya;C. Talmo;Brian L. Hollenbeck;David Mattingly;Ruijia Niu;David C. Chang;Eric L Smith
通讯作者：
Eric L Smith