# Engineering Effective T cell Immunity to Multiple Myeloma

> **NIH NIH P01** · FRED HUTCHINSON CANCER CENTER · 2024 · $850,024

## Abstract

ABSTRACT
Curative therapy for multiple myeloma remains elusive despite remarkable advances in drug therapy, biologics
and autologous hematopoietic stem cell transplant. Adoptive cell therapy using T cells modified by gene transfer
to express synthetic chimeric antigen receptors (CAR-T) that retarget specificity to a surface molecule expressed
on myeloma cells is an exciting advance and has been highly effective for reducing tumor burden and inducing
complete responses in a fraction of patients with refractory disease. Although the initial responses to CAR-T are
impressive, relapses are frequent and heterogeneity in the expression of target antigens on the tumor and lack
of CAR-T persistence have been identified as underlying causes for disease recurrence. The premise of this
proposal is that these barriers can be overcome by advanced approaches to T cell engineering. We will design
novel synthetic hybrid T cell receptors that have markedly greater Ag sensitivity compared to CAR-T and
simultaneously target more than one MM antigen to prevent escape of tumor cells expressing low levels of or
lacking a single antigen. A new approach that instructs memory and stemness transcriptional and epigenetic
states in engineered T cells that have been associated with superior T cell persistence after adoptive transfer
will be developed to improve therapeutic efficacy. Further advances in adoptive T cell therapy will be necessary
and should be informed by a comprehensive understanding of other mechanisms that enable rare myeloma cells
to persist in the bone marrow tumor microenvironment and regrow. We have assembled a rich resource of blood
and bone marrow samples obtained from patients prior to and at multiple time points after treatment with BCMA
targeted CAR-T cell and will use high dimensional analytic techniques to identify tumor intrinsic and extrinsic
mechanisms associated with response and relapse. By employing cutting edge synthetic biology and
immunologic techniques we will accelerate development of more effective immunotherapies for MM. The specific
aims are:
Aim 1: Design and evaluate highly sensitive chimeric TCRs that recognize two myeloma Ag.
Aim 2: Determine if inducing a memory stem cell phenotype in MM-specific T cells through CD27
costimulation improves antitumor efficacy.
Aim 3: Determine mechanisms of resistance in MM patients receiving BCMA CAR-T alone or
combined with a gamma secretase inhibitor.

## Key facts

- **NIH application ID:** 10935586
- **Project number:** 2P01CA018029-48A1
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** STANLEY R. RIDDELL
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $850,024
- **Award type:** 2
- **Project period:** 1997-08-28 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935586

## Citation

> US National Institutes of Health, RePORTER application 10935586, Engineering Effective T cell Immunity to Multiple Myeloma (2P01CA018029-48A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10935586. Licensed CC0.

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