# Activating Native Tumor Immunity with IL-33 Armored CARs

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2024 · $546,511

## Abstract

ABSTRACT
Unlike liquid cancers, current CAR T cell immunotherapies have little effect against solid cancers, largely due to
the immunosuppressive nature of the tumor microenvironment. The race between administered CAR T cells and
tumor associated cells to kill off and/or neutralize the other is tipped heavily in favor of the tumor. Heterogeneous
tumors or tumors able to shed or downregulate CAR-targeted antigens can also escape elimination by functional
CAR T cell effectors. We recently found that CAR T cells delivery of dual cytokines can enlist and activate
endogenous T cells, NK cells and myeloid cells to mount an effective anti-tumor immune response. Further
investigation revealed that perforin and IFNγ are dispensable in CAR T cells, supporting an accessory role for
CAR T cells in mobilizing endogenous immune cells to ultimately control tumor growth. CAR T cell-mediated
dual cytokine delivery was effective in controlling tumor growth with 3 different CAR T cell constructs and 4 in
vivo tumor models: primary and metastatic melanoma and primary colon cell carcinoma mouse models, and
importantly was impervious to antigen loss. This suggests that the dual cytokine platform has potential for
universal application against multiple solid tumor types. In this application, we hypothesize that CAR T cell
delivery of dual cytokines has broad application because it counteracts immunosuppressive innate and adaptive
immune cells to elicit a broad endogenous anti-tumor response independent of CAR effector potential. We will
test this hypothesis by identifying CAR T cell survival and distribution dynamics (Aim 1), identify the common
and tumor-specific changes in immunosuppressive, immunostimulatory and effector leukocyte populations
isolated from poorly and strongly immunogenic tumors pre- and post-CAR cytokine treatment (Aim 2), and
determine their roles in activating endogenous tumor immunity (Aim 3). The cellular and mechanisms identified
will support further improvement and clinical translation of the Super2+IL-33 platform with various CAR targeting
constructs for CAR T cell therapies for solid tumors.

## Key facts

- **NIH application ID:** 10843238
- **Project number:** 5R01CA271553-02
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Yina Hsing Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $546,511
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843238

## Citation

> US National Institutes of Health, RePORTER application 10843238, Activating Native Tumor Immunity with IL-33 Armored CARs (5R01CA271553-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10843238. Licensed CC0.

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