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.

Public Health Relevance

CAR T cell therapy targeting BCMA for advanced multiple myeloma (MM) leads to a high overall response rate, however, with durability limited in many patients mediated by target antigen loss or lack of CAR T cell expansion/functional persistence. Our work aims to better understand mechanisms of relapse post-CAR T cell therapy in the setting of the MM tumor microenvironment by studying patient marrow immune cells in a humanized mouse model and samples from MM patients treated on CAR T cell clinical trials. We will compare novel CAR T cell strategies targeting dual-antigens to mitigate antigen escape, and ?armored? CAR T cell strategies to mitigate MM tumor microenvironment immune suppression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA241400-01
Application #
9805797
Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Lim, Susan E
Project Start
2019-08-01
Project End
2024-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065