Identification and Characterization of Regorafenib and NU7441 as Targeted Immunotherapies for Melanoma
AdvisorDavila, Eduardo, Ph.D.
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AbstractThe emergence of new therapeutics, including targeted therapies and immunotherapies, has improved prognoses for melanoma patients. Yet, each class of therapy suffers from unique shortcomings. Targeted therapies are only approved for approximately half of melanoma patients that carry a certain mutation in the BRAF gene. Additionally, responses to targeted therapies are almost always transient, as resistance arises rapidly. Immunotherapies offer, for the first time, the potential for long-term responses and complete regressions. However, these remarkable responses only occur in a small fraction of patients. The use of combination therapies is therefore emerging as a popular strategy to further improve outcomes in melanoma patients. The challenge is to identify appropriate agents that can be rationally combined to improve patient responses. We hypothesized that a targeted therapeutic that also altered the immunoregulatory milieu in a tumor might best synergize with an immunotherapy. Toward this end, high-throughput flow cytometry-based screening was performed with two large and diverse drug libraries to identify candidate therapies that augment T cell immunotherapy efficacy. Two lead therapies, regorafenib and NU7441, were selected based on their ability to alter a variety of immunomodulatory proteins, including CD55, CD73, CD155, programmed death ligand 1 (PD-L1), nerve growth factor receptor (NGFR), and human leukocyte antigen (HLA) class I in a heterogeneous panel of melanomas. The therapies were also found to upregulate several melanoma antigens, inhibit proliferation, and perturb commonly activated oncogenic signaling pathways in melanomas. T cells treated with the therapies proliferated normally and expressed increased CD25, CD28, inducible T cell costimulator (ICOS), and reduced co-inhibitory receptors. These phenotypic changes were associated with improved T cell function. In murine models, the compounds suppressed melanoma progression and altered various T cell subsets in the tumor microenvironment when used with and without various immunotherapies. Finally, regorafenib skewed intratumoral macrophages away from a phenotype associated with pro-tumor function. Collectively, these studies demonstrate for the first time that regorafenib and NU7441 influence the expression of immunomodulatory proteins on both tumor cells and T cells, and enhance the efficacy of various immunotherapies.
DescriptionUniversity of Maryland, Baltimore. Molecular Medicine. Ph.D. 2017
Molecular Targeted Therapy