# Enhancing CAR-T cell therapy through theranostic targeted radionuclide therapy

> **NIH NIH R21** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $415,260

## Abstract

PROJECT SUMMARY
Chimeric antigen receptor (CAR)-T cell therapy has emerged as a powerful new class of living medicines for
cancer therapy, especially for patients with resistant or refractory blood cancers. However, application of CAR-
T cell therapy to solid cancers has had little success, due to challenges of heterogenous antigen expression,
limited tumor infiltration and CAR-T cell dysfunction in the immunosuppressive tumor microenvironment.
Combinatorial treatment approaches, such as integration of radiotherapy to CAR-T cells, may provide an
effective strategy to propagate antitumor immunity and overcome obstacles posed by solid tumors. In a
preliminary study using CAR-T cells co-expressing somatostatin receptor 2 (SSTR2) for the targeted delivery
of an immunomodulatory dose of 177Lu-DOTATATE, we noted rapid tumor localization of 177Lu-DOTATATE and
subsequent regression of large established tumors. Furthermore, our preliminary data show an increase in
serum IFN-γ and perforin following treatment with 177Lu-DOTATATE, suggesting a radiation-induced effect on
T-cell immunity. Our objective in this R21 proposal is to explore the potential of target radiotherapy (TRT),
delivered systemically through SSTR2-expressing CAR-T cells and an FDA-approved theranostic
endoradiotherapy (177Lu-DOTATATE, Lutathera), to enhance CAR-T cell therapy. Our Specific Aims are to: 1)
Investigate the impact of image-guided TRT on antitumor immune responses. We hypothesize that an
optimized TRT dose can inflame tumors, rendering them more susceptible to T-cell cytotoxicity and thereby
facilitating tumor eradication. Guided by CAR-T cell imaging and dosimetry estimation, we will conduct a dose
response study to identify the optimal radiation dose for this innovative combination therapy. Additionally,
utilizing a heterogenous tumor model, we will explore the potential of immunomodulatory TRT to promote
tumor killing through TRAIL- and Fas-mediated mechanisms, partially independent of CAR-T cells. This
approach holds the promise of addressing some mechanisms of tumor resistance, such as antigen escape. 2)
Elucidate the underlying mechanism for the synergistic combination of TRT and CAR-T cell therapy.
Using the syngeneic mouse model with an intact immune system and tumor microenvironment, we aim to
validate and elucidate key phenotypic behaviors and molecular pathways driving the synergy between
immunomodulatory low-dose TRT and CAR-T cell therapy. Our experimental approach will encompass
techniques such as flow cytometry, immunohistochemistry, and single cell multi-omics analysis. The proposed
work offers a new strategy for combining endoradiotherapy with CAR-T cell therapy that will be applicable to
systemic disease with widespread metastases. Furthermore, it will add mechanistic insights in understanding
the immunomodulatory effects of radiation.

## Key facts

- **NIH application ID:** 10946201
- **Project number:** 1R21CA292224-01
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Moonsoo M. Jin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $415,260
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10946201

## Citation

> US National Institutes of Health, RePORTER application 10946201, Enhancing CAR-T cell therapy through theranostic targeted radionuclide therapy (1R21CA292224-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10946201. Licensed CC0.

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