# Enhancing CAR T therapy in multiple myeloma

> **NIH NIH R21** · DUKE UNIVERSITY · 2022 · $225,803

## Abstract

SUMMARY OF WORK
Our long-term goal is to develop novel approaches to enhance the efficacy of chimeric antigen receptor (CAR) T
therapy. CAR T cell therapy targeting B-cell maturation antigen (BCMA) has shown great promise in the treatment
of relapsed and/or refractory (RR) multiple myeloma (MM). However, even with relatively short follow-up relapse
eventually occurs in over half of all patients with a median progression-free survival of only 11.8 months (Raje et
al. N Engl J Med 2019; 380:1726). A better understanding of the mechanisms of myeloma relapse and resistance
to CAR T therapy is urgently needed and will lead to improved CAR T therapy. Myeloid-derived suppressor cells
(MDSCs) are a heterogeneous population of cells consisting of monocytic MDSCs and granulocytic MDSCs.
MDSCs inhibit T cell function and are thought to play an important role in CAR T therapy resistance/relapse. The
addition of MDSC depleting therapy increases CAR T efficacy in solid tumor models (Long et al. Cancer Immunol
Res 2016; 4:869). Recently we have found that patients with RRMM had significantly elevated Gr-MDSCs.
Additionally, we found that an increase of MDSCs correlated with the development of MM in a transplantable
VK*MYC mouse myeloma model. Interestingly, compared to wild-type or sphingosine kinase 1 (SK1) knockout
mice, sphingosine kinase 2 (SK2) knockout mice were completely free of myeloma after being injected with
VK*MYC myeloma cells and showed significantly reduced numbers of MDSCs. Furthermore, treatment with a
specific SK2 inhibitor (ABC294640, YELIVAÒ) eliminated both human and mouse MDSCs. ABC294640 showed
an excellent safety profile in our recently completed phase I study in patients with RRMM (NCT02757326). The
objective of this application is to determine the efficacy of combining SK2 inhibition with CAR T therapy in the
treatment of MM. Our central hypothesis is that the combination of SK2 inhibitor and CAR T therapy will enhance
the response and duration of the CAR T therapy by reducing the number of MDSCs. We have three specific aims.
Aim 1 is to determine the efficacy of the combination of SK2 inhibitor (ABC294640) and CAR T therapy in vivo in
a fully immunocompetent, syngeneic myeloma CAR T therapy mouse model. We will determine the efficacy of
combining ABC294640 with mouse BCMA-targeted CAR T cell therapy in vivo. Aim 2 is to determine the
mechanisms through which SK2 regulates MDSCs. We will determine the effects of SK2 on MDSC differentiation
and function and on the S1P-STAT3/HDAC-1/2- ROR-gt pathway. Aim 3 is to measure the number and function
of MDSCs over time in hematologic malignancy patients treated with CAR T therapy and determine the correlation
between MDSCs and disease relapse/resistance to CAR T therapy. Our research is innovative, because it
represents a new and substantive departure and significant advance from the status quo by understanding the
roles of MDSCs and SK2 in CAR T therapy. Our study will fundamentally advance o...

## Key facts

- **NIH application ID:** 10355867
- **Project number:** 1R21CA267275-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Yubin Kang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $225,803
- **Award type:** 1
- **Project period:** 2022-03-08 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355867

## Citation

> US National Institutes of Health, RePORTER application 10355867, Enhancing CAR T therapy in multiple myeloma (1R21CA267275-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10355867. Licensed CC0.

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