Arginase therapy combines effectively with checkpoint blockade or agonist anti-OX40 immunotherapy to control tumor growth.

Metabolic dysregulation is a hallmark of cancer; for instance, many tumors exhibit auxotrophy for various amino acids, such as arginine, as they are unable to meet the demand for these amino acids through endogenous production. This vulnerability can be exploited by employing therapeutic strategies that deplete systemic arginine in order to limit the growth and survival of arginine auxotrophic tumors. Pegzilarginase, a human arginase 1 enzyme engineered to have superior stability and enzymatic activity relative to the native human arginase 1 enzyme, depletes systemic arginine by converting it to ornithine and urea. Therapeutic administration of pegzilarginase in the setting of arginine auxotrophic tumors exerts direct anti-tumor activity by starving the tumor of exogenous arginine. We hypothesized that in addition to this direct effect, pegzilarginase treatment indirectly augments anti-tumor immunity through increased antigen presentation, thus making pegzilarginase a prime candidate for combination therapy with immuno-oncology (I-O) agents. Indeed, tumor-bearing mice (CT26; MC38; MCA-205) receiving pegzilarginase in combination with aPD-L1 or agonist aOX40 mAb experienced significantly increased survival relative to animals receiving I-O monotherapy. Combination pegzilarginase/immunotherapy induced robust anti-tumor immunity characterized by increased intratumoral effector CD8+ T cells and M1-polarization of tumor-associated macrophages. Our data suggests potential mechanisms of synergy between pegzilarginase and I-O agents that include increased intratumoral MHC expression on both APCs and tumor cells, and increased presence of M1-like anti-tumor macrophages. These data support the clinical evaluation of I-O agents in conjunction with pegzilarginase for the treatment of patients with cancer