# Project 3. Overcoming Melanoma Treatment Resistance with Cytokine Immunotherapy

> **NIH NIH P50** · YALE UNIVERSITY · 2023 · $383,419

## Abstract

PROJECT 3: PROJECT SUMMARY
Major changes have occurred in treatment of unresectable melanoma in the last decade in which immune-based
therapies have dramatically enhanced overall survival. Unfortunately, almost half the melanoma patients do not
respond to immune checkpoint inhibitors (ICI) upfront, and others develop recurrent or resistant disease over
time. Immunotherapies that can stimulate immunity in ICI-resistant melanoma are still therefore urgently needed.
To this end, cytokines have potent immunostimulatory activities that make them attractive candidates for use in
combination with ICIs to overcome resistance. Interleukin 18 (IL-18) is particularly appealing, because the IL-18
receptor (IL-18R) is specifically upregulated in CD8 tumor infiltrating lymphocytes and is widely expressed on
natural killer (NK) cells. However, clinical trials of recombinant IL-18 were unsuccessful, likely due to upregulation
of the endogenous IL-18 receptor antagonist or IL-18 binding protein, IL-18BP, which inhibits the
immunostimulatory effects of IL-18. The Ring lab therefore created an engineered version of IL-18 that is
resistant to the IL-18BP but fully retains its ability to activate the IL-18R. A clinical grade “decoy resistant” IL-18
(DR18) has been developed and licensed to Simcha Therapeutics by Yale University (ST-067). ST-067 is
currently being investigated in a first-in-human clinical trial as monotherapy. In pre-clinical models, DR18
synergizes with anti-PD-1. Furthermore, in murine models, DR-18 is highly effective in treating ICI-resistant MHC
class I deficient tumors, consistent with the ability of IL-18 to also activate NK cells. We hypothesize that
combining DR-18 with immune checkpoint inhibitors can overcome ICI resistance in melanoma via
activation of NK cells, T effector cells and stem-like memory T cells. We propose to conduct a series of pre-
clinical studies (Aim 1) utilizing novel animal models developed in house with clinically relevant melanoma
mutations to determine the mechanism of response and resistance of the combination of DR-18 with clinically
approved ICIs (inhibitors of PD-1, CTLA-4 and LAG-3). We have engineered the murine models to enable
evaluation of antigen-specific T cell responses to determine how T effector and memory function is improved.
Seeing that class I MHC loss in tumor cells is a major cause of resistance to anti-PD-1 in humans, we will also
study effects of DR-18 alone and with ICIs in B2m knockout models (MHC-I deficient). In Aim 2 we will conduct
a phase I/II clinical trial of ST-067 with immune checkpoint inhibitors in patients whose disease has progressed
on a prior regimen containing anti-PD-1. Tumor and blood samples from patients enrolled in the trial will be
interrogated to determine cellular mechanisms of response/resistance in humans using cutting-edge spatial
transcriptomics methods developed at Yale, and results will be compared to the murine samples collected in Aim
1. If successful, these stu...

## Key facts

- **NIH application ID:** 10711513
- **Project number:** 2P50CA121974-16
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Aaron Michael Ring
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $383,419
- **Award type:** 2
- **Project period:** 2006-06-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10711513

## Citation

> US National Institutes of Health, RePORTER application 10711513, Project 3. Overcoming Melanoma Treatment Resistance with Cytokine Immunotherapy (2P50CA121974-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10711513. Licensed CC0.

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