# Development of a tumor-activated IL12 prodrug to treat solid tumors

> **NIH NIH F30** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $36,545

## Abstract

Project Summary/Abstract:
Despite recent advances in cancer immunotherapy, solid tumors remain largely refractory to treatment due to
disruption of immune homeostasis by the tumor microenvironment (TME). Within the TME, a combination of
hypoxia, acidity, suppressive cells, and immune checkpoints leads to poor differentiation of type I effector cells,
preventing the development of a robust immune response. IL12 is a naturally produced cytokine that can directly
induce type I, cell-mediated immunity through the IL12Rβ1/IL12Rβ2 complex on innate lymphoid cells (ILCs)
and T cells. IL12 has been remarkably successful against solid tumors in preclinical trials, but its clinical
development has been impaired by lethal toxicity due to systemic immune overactivation. I have developed a
novel IL12-based prodrug (proIL12) that displays no noticeable toxicity in vivo but maintains full antitumor
efficacy. The kinetics and cellular mechanism of proIL12 must still be ascertained, but preliminary data suggests
T cells play a critical role and IFNγ is the main cytokine induced. Therefore, I hypothesize that proIL12 circulates
in inert prodrug form until activated by tumor-specific enzymes, at which point it activates T cells directly through
IL12 receptor and secondarily through IFNγ production. To test my hypothesis, I will first validate proIL12’s drug
profile by determining an optimal dosing schedule, monitoring tumor-specific activation, and measuring toxicity.
Then, I will explore which specific cell subtypes among ILCs and T cells are necessary to reject tumors. Finally,
I will independently assess the downstream role of IFNγ in coordinating the proIL12 response. By systematically
characterizing both physical and mechanistic properties of proIL12, I will not only prepare it for further clinical
development but also inform future steps such as combination therapies or prognostic markers. As a whole, my
study will produce a tolerable immunotherapeutic agent capable of reversing TME-induced immune disarray to
eliminate solid tumors.

## Key facts

- **NIH application ID:** 10152759
- **Project number:** 1F30CA254023-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Benjamin Moon
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $36,545
- **Award type:** 1
- **Project period:** 2021-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152759

## Citation

> US National Institutes of Health, RePORTER application 10152759, Development of a tumor-activated IL12 prodrug to treat solid tumors (1F30CA254023-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10152759. Licensed CC0.

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