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

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2021 · $252,737

## Abstract

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 ap...

## Key facts

- **NIH application ID:** 10248364
- **Project number:** 5K08CA241400-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Eric L Smith
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $252,737
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248364

## Citation

> US National Institutes of Health, RePORTER application 10248364, Understanding and addressing sub-optimal responses to CAR T cell therapy for Multiple Myeloma (5K08CA241400-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10248364. Licensed CC0.

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