# P38 MAPK is a molecular switch that controls the acquired resistance in adoptive cell therapy

> **NIH NIH R37** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2022 · $368,487

## Abstract

Project Summary
A major obstacle to successful adoptive cell therapy (ACT) is the development of acquired resistance, which
can occur due to cancer cells become invisible to tumor-specific T cells when cancer cells downregulate or lost
the antigen(s) (refers to antigen-low/loss resistant tumor cells, or ALRs). In this proposal, we will explore the
role of reprogramming of tumor microenvironment (TME) by p38 MAPK inhibition to promote a robust dendritic
cell (DC)-driving anti-ALR immunity to prevent acquired resistance in ACT. In our in vivo preliminary studies,
co-treatment with CAR T cells and Ralimetinib (a potent and selective inhibitor of p38 MAPK developed for
cancer patients) confers immunogenic DC signature characteristics within TME. Strikingly, CAR T
cell+Ralimetinib-treatment eradicated established tumors and resulted in long-term tumor-free survival by
triggering a robust host anti-ALR immunity, whereas CAR T cell ACT alone recapitulated the clinical scenario
of cancer relapse mediated by ALRs. Based on these novel findings, we hypothesize that p38 MAPK is a
critical molecular switch that controls DC differentiation, where p38 inhibition promotes an immunogenic DC
transcriptional program and induces potent anti-ALR immunity to prevent the acquired resistance in T cell
therapy. Aim 1 will determine the role of NFB/Stat5 signaling by repression of PPAR in the molecular
mechanisms of Ralimetinib-mediated DC enrichment. Aim 2 will determine the role of NFB (p50)-dependent
viral mimicry in DCs for ALR clearance after p38 inhibitor-treatment in vivo. This study may uncover a novel
mechanism for preventing tumor relapse in ACT. Data from our proposed Aims may yield critically needed
evidence that repurposing the clinically tested Ralimetinib from targeting p38 MAPK in tumor cells toward that
of immune cells may induce a complete and durable response in ACT. This translationally relevant work could
then lay the foundation for future clinical trials.

## Key facts

- **NIH application ID:** 10407010
- **Project number:** 5R37CA251318-04
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Yong Lu
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,487
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407010

## Citation

> US National Institutes of Health, RePORTER application 10407010, P38 MAPK is a molecular switch that controls the acquired resistance in adoptive cell therapy (5R37CA251318-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10407010. Licensed CC0.

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