DRP-104, a novel broad acting glutamine antagonist, has significant therapeutic potential in cancer via directly targeting tumor metabolism and inducing a potent antitumor immune response. Here we sought to elucidate the immunomodulatory effect of DRP-104 on tumor growth inhibition as a single agent and in combination with PD-1/PD-L1 checkpoint inhibitors in syngeneic models. We utilized multiple technologies to assess mechanistic effects on immune cells in vivo including flowcytometry, multiplex immunoassay, gene expression profiling and GeoMx™ digital spatial profiling.

DRP-104 mediated tumor growth inhibition was associated with increased tumor-infiltrating leukocytes (TIL) including T, NKT, and NK cells, M1-polarized tumor associated macrophages, and decreased immunesuppressive cells such as MDSCs. Nanostring® IO360 analysis revealed broad immunological modulation such as increase in cytotoxicity/antigen presentation score; increase in tumor metabolic stress/apoptotic score; and decrease in cell proliferation score. GeoMx® profiling also demonstrated increased tumoral T cells and granzyme B expression. DRP-104 showed significant tumor growth inhibition and regressions as a single agent in mouse syngeneic tumor models, including those resistant to immune checkpoint inhibitors. Lastly, combination of DRP-104 with anti-PD-1 Ab or anti-PD-L1 Ab further improved survival effect with long-term durable cures.