# Improving response durability after CAR T cell therapy for multiple myeloma

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $565,591

## Abstract

PROJECT SUMMARY / ABSTRACT (PROJECT 3)
Multiple myeloma (MM) is a hematologic malignancy of bone marrow plasma cells. Even though MM is almost
universally fatal, modern therapy has markedly improved survival. Among the most promising new MM therapies
are CAR T cells targeting B cell maturation antigen (BCMA). Despite high response rates in patients with
advanced disease, however, almost all patients eventually relapse after current-generation anti-BCMA CAR T
cells. This proposal furthers a long-term goal to prevent late relapse in MM patients after initial response to CAR
T cell therapy. In most cases, BCMA expression is retained at relapse, suggesting loss of anti-BCMA immune
surveillance as the primary mode of treatment failure. We and others have found that features of the T cells used
for CAR T cell manufacturing predict clinical outcomes, that CAR T cells can occasionally proliferate at late
timepoints post-infusion to control progressive disease, and that features of the bone marrow microenvironment
predict relapse risk after anti-BCMA CAR T cells. This proposal undertakes new approaches to prevent late MM
relapse after CAR T cell therapy; the approache to the clinical and pre-clinical studies is rooted in these prior
observations. We will conduct a clinical trial to test the safety and feasibility of therapy with anti-BCMA CAR T
cells manufactured from marrow-infiltrating lymphocytes (MIL) rather than the peripheral blood lymphocytes
traditionally used in CAR T cell manufacturing. We hypothesize that the BM-homing capability of MILs will
enhance trafficking and persistence of CAR T cells in BM. We will also pre-clinically develop two new approaches
to modulate CAR T cell activity in vivo post infusion. (1) We will introduce a modified IL-2 receptor into CAR T
cells to enable selective post-infusion in vivo stimulation with a pharmacologically administered and orthogonally
modified IL-2 ligand (orthoIL2); we hypothesize that orthoIL2 can prevent late relapse by maintaining in vivo anti-
BCMA immune surveillance. (2) We will develop BCMA-encoding mRNA-containing lipid nanoparticles (mRNA-
LNPs) to present BCMA in the context of antigen-presenting cells outside the immunosuppressive MM
microenvironment; we hypothesize that BCMA-encoding mRNA-LNPs can prolong in vivo anti-BCMA immune
surveillance, providing an approach to post-infusion modulation of CAR T cell activity that could be rapidly and
cost-effectively translated in combination with established, FDA-approved anti-BCMA CAR T cell therapies.
Collectively, our proposed studies will generate clinical and pre-clinical data to support the development of early-
phase clinical trials promising new approaches to prevent relapse after CAR T cell therapy for MM, which is the
primary clinical problem facing the field. In addition, findings from our studies could be readily translated to other
cancer types, including solid tumors.

## Key facts

- **NIH application ID:** 10931423
- **Project number:** 5P01CA214278-07
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael C. Milone
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $565,591
- **Award type:** 5
- **Project period:** 2017-08-15 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931423

## Citation

> US National Institutes of Health, RePORTER application 10931423, Improving response durability after CAR T cell therapy for multiple myeloma (5P01CA214278-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10931423. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*