# Engineering In Vivo Chimeric Antigen Receptor Macrophages (CARMs) using mRNA-exosomes for Cancer Immunotherapy

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $539,426

## Abstract

PROJECT SUMMARY
 Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic
cancers. However, for solid tumors, CAR T cells face challenges including intratumor heterogeneity, dynamic
expression of target receptors, and often the inability for T cells to traffic to tumors to mediate the desired
antitumor effect. In contrast to the lack of T cell infiltrates, many solid tumors are abundant in immune
suppressive myeloid cells including macrophages. Therefore, converting these immune suppressive cells into
tumoricidal phenotype represents a promising strategy for cell-based therapy. There are now strong interest in
generating CAR macrophages in which autologous macrophages are transduced with CAR delivered by viral
vectors ex vivo to enhance their phagocytosis, antigen presentation and cytokine producing capabilities
following re-infusion. However, ex vivo preparation of CAR macrophages is complex, time consuming, and due
to the non-dividing nature of macrophages, is often inefficient. With the recent advances in mRNA-based
therapeutics, it is now possible to reprogram specific immune cell populations in vivo, thus eliminating the
complex ex vivo production of autologous CAR cells. Our present proposal aims to propose an innovative
strategy of generating CAR macrophages in vivo using mRNA-loaded exosomes to treat HER2 receptor
positive breast cancer. This will be the first study to evaluate the feasibility of producing CAR macrophages in
vivo using mRNA delivery platforms and assessing the antitumor efficacy of CAR macrophages for cancer
immunotherapy. We hypothesize that our strategy represents a revolutionary way to produce CAR
macrophages in vivo using CAR mRNA-loaded exosome and offers a promising new approach for cell therapy
against solid tumors. Our previous study showed that we can efficiently produce mRNA-loaded exosomes to
restore protein expression in solid tumors. Furthermore, our preliminary experiments showed that the
exosomes loaded with HER2 CAR mRNA can produce CAR macrophages in vivo with enhanced effector
functions. Our current study will test our overall hypothesis by using the following specific aims. In Aim 1, we
will evaluate the dynamics and toxicity of CAR macrophage production in vivo using CAR mRNA exosomes. In
Aim 2, we will evaluate transcriptomic and functional profiles of in vivo generated CAR macrophages, Finally,
in Aim 3, we will assess the antitumor effect of in vivo generated CAR macrophages against both murine and
human HER2 expressing breast cancer. If successful, our proposed research can overcome a major technical
hurdle that is currently facing cell therapy. The mRNA exosome platform could potentially be expanded to other
CAR constructs and greatly expand the potential utility of cell therapy for breast and other solid cancers.

## Key facts

- **NIH application ID:** 10890157
- **Project number:** 5R01CA284108-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Wen Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $539,426
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890157

## Citation

> US National Institutes of Health, RePORTER application 10890157, Engineering In Vivo Chimeric Antigen Receptor Macrophages (CARMs) using mRNA-exosomes for Cancer Immunotherapy (5R01CA284108-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890157. Licensed CC0.

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