Project 3. Overcoming Melanoma Treatment Resistance with Cytokine Immunotherapy

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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 studies will support further development of ST-067 with ICIs in patient subsets carefully defined by immune cell characteristics. This approach can be applied to patients with other types of anti-PD-1 resistant tumors as well, and these studies have the potential for far-reaching implications.