nu-7441 and regorafenib

Combination therapies have the potential to improve outcomes in melanoma patients but have not yet been clinically efficacious. Here, we used high-throughput flow cytometry-based screening to identify and characterize candidate therapies that might synergize with and augment T-cell immunotherapy efficacy. Two lead therapies, regorafenib (Reg) 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 HLA class I in a heterogeneous panel of melanomas. The therapies also upregulated several melanoma antigens, inhibited proliferation, and perturbed activation of oncogenic signaling pathways in melanomas. T cells treated with the therapies proliferated normally and exhibited a favorably altered phenotype, including increased CD25, CD28, inducible T-cell costimulator (ICOS), and reduced expression of coinhibitory receptors. Cytokine production was also increased in treated T cells. When administered in mice, REg suppressed melanoma progression in a CD8

Topics: 5'-Nucleotidase; Animals; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; CD55 Antigens; CD8-Positive T-Lymphocytes; Cell Proliferation; Chromones; Flow Cytometry; Genes, MHC Class I; Humans; Immunomodulation; Immunotherapy; Melanoma; Mice; Morpholines; Phenylurea Compounds; Pyridines; Receptors, Virus; T-Lymphocyte Subsets; Tumor Microenvironment