# A PLATFORM TECHNOLOGY TO GENETICALLY REPROGRAM CANCER CELLS FOR ENHANCED IMMUNOTHERAPY

> **NIH NIH R37** · JOHNS HOPKINS UNIVERSITY · 2021 · $374,578

## Abstract

PROJECT SUMMARY
 Advances in cancer immunotherapy have great potential for treating tumors that are refractory to
conventional treatments, and T cells primed ex vivo by natural or artificial antigen-presenting cells (APCs) to
target and kill cancer cells have been shown clinically to improve survival in patients with highly aggressive
cancers. APCs normally prime T cells by presenting a tumor antigen-specific signal 1, consisting of a major
histocompatibility complex (MHC) I molecule with a tumor antigen peptide; a co-stimulatory signal 2 that directs
the action of the T cells upon recognition of the tumor; and a secreted signal 3 for recruitment and activation of
immune cells. Instead of engineering the patient's APCs to direct a T-cell response against a tumor or
fabricating artificial, synthetic APCs, both of which are costly, complex, and/or patient-specific processes, we
propose to reprogram cancer cells themselves to become tumor-derived APCs (tAPCs). Because tumor
cells already intrinsically express signal 1 (tumor antigen in the context of MHC I), they can be engineered in
situ to express the other necessary signals and therefore act as APCs, directing cytotoxic T-cell responses
against themselves. Tumor cells with low MHC I expression will stimulate natural killer (NK) cells to aid this
purpose. We have designed synthetic, non-viral nanoparticles that can deliver DNA to cancer cells with high
efficacy and specificity over healthy tissue, and we will inject these into a tumor mass to induce expression of
signal 2 and signal 3, using two different in vivo orthotopic tumor models (melanoma and triple-negative breast
cancer) and four in vitro tumor models as examples. Our proposed experiments will first optimize the
nanoparticle formulation for high expression and cancer specificity in vitro and in vivo. We will then
demonstrate activation and T and NK cells after reprogramming of cancer cells to express signals 2 and 3
along with signal 1 both in vitro and in vivo. Finally, we will show anti-cancer efficacy after intratumoral injection
of these nanoparticles in immunocompetent murine cancer models, with a focus on models of metastasis, and
examine the immunological mechanisms underlying our technology. Importantly, because our goal is to use
DNA-delivery nanoparticles to stimulate the immune system to kill cancer cells, rather than directly killing the
melanoma cells by gene transfer, our strategy requires only a representative subset of malignant cells to be
successfully transfected. If successful, this could result in an affordable, fully synthetic, local, antigen-agnostic
therapy that nevertheless leads to antigen-specific systemic immune rejection of tumors.

## Key facts

- **NIH application ID:** 10206076
- **Project number:** 5R37CA246699-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Stephany Yi Tzeng
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,578
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206076

## Citation

> US National Institutes of Health, RePORTER application 10206076, A PLATFORM TECHNOLOGY TO GENETICALLY REPROGRAM CANCER CELLS FOR ENHANCED IMMUNOTHERAPY (5R37CA246699-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10206076. Licensed CC0.

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