IL15 and Anti-PD-1 Augment the Efficacy of Agonistic Intratumoral Anti-CD40 in a Mouse Model with Multiple TRAMP-C2 Tumors

Purpose: IL15 promotes activation and maintenance of natural killer (NK) and CD8 thorn T effector memory cells making it a potential immunotherapeutic agent for the treatment of cancer. However, monotherapy with IL15 was ineffective in patients with cancer, indicating that it would have to be used in combination with other anticancer agents. The administration of high doses of common gamma chain cytokines, such as IL15, is associated with the gener-ation of "helpless" antigen-nonspecific CD8 T cells. The generation of the tumor-specific cytotoxic T cells can be mediated by CD40 signaling via agonistic anti-CD40 antibodies. Nevertheless, parenteral administration of anti-CD40 antibodies is associated with unaccept-able side effects, such as thrombocytopenia and hepatic toxicity, which can be avoided by intratumoral administration. Experimental Design: We investigated the combination of IL15 with an intratumoral anti-CD40 monoclonal antibody (mAb) in a dual tumor TRAMP-C2 murine prostate cancer model and expand-ed the regimen to include an anti-PD-1 mAb. Results: Here we demonstrated that anti-CD40 given intra-tumorally not only showed significant antitumor activity in treated tumors, but also noninjected contralateral tumors, indicative of abscopal efficacy. The combination of IL15 with intratumoral anti-CD40 showed an additive immune response with an increase in the number of tumor-specific tetramer-positive CD8 T cells. Furthermore, the addition of anti-PD-1 further improved efficacy mediated by the anti-CD40/IL15 combination. Conclusions: These studies support the initiation of a clinical trial in patients with cancer using IL15 in association with the checkpoint inhibitor, anti-PD-1, and intratumoral optimized anti-CD40.