Chen et al. demonstrated that intratumoral anti-CD40 administration in combination with intraperitoneal mIL-15 enhanced antitumor immunity and prolonged survival in the injected and non-injected distal TRAMP-C2 tumors compared to monotherapy. The antitumor efficacy of the combination therapy was CD8+ and, surprisingly, CD4+ T cell-dependent, and led to increases in absolute numbers of CD44high CD8+ T cells and TRAMP-C2 tumor-specific Spas-1/SNC9-H8 CD8+ T cells in PBMCs, associated with protection against rechallenge. Inclusion of anti-PD-1 was additive to anti-CD40 and IL-15 combinations, and further enhanced antitumor activity.
Contributed by Shishir Pant
PURPOSE: IL-15 promotes activation and maintenance of natural killer (NK) and CD8+ T-effector memory (TEM) cells making it a potential immunotherapeutic agent for the treatment of cancer. However, monotherapy with IL-15 was ineffective in cancer patients, indicating that it would have to be used in combination with other anticancer agents. The administration of high doses of common gamma chain (_c) cytokines, such as IL-15, is associated with the generation of "helpless" antigen-nonspecific CD8 T-cells. The generation of the tumor-specific cytotoxic T-cells (CTLs) can be mediated by CD40 signaling via agonistic anti-CD40 antibodies. Nevertheless, parenteral administration of anti-CD40 antibodies is associated with unacceptable side effects, such as thrombocytopenia and hepatic toxicity, which can be avoided by intratumoral administration. EXPERIMENTAL DESIGN: We investigated the combination of IL-15 with an intratumoral anti-CD40 monoclonal antibody (mAb) in a dual tumor TRAMP-C2 murine prostate cancer model and expanded the regimen to include an anti-PD-1 mAb. RESULTS: Here we demonstrated that anti-CD40 given intratumorally not only showed significant antitumor activity in treated tumors, but also uninjected contralateral tumors, indicative of abscopal efficacy. The combination of IL-15 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 anti-PD-1 further improved efficacy mediated by the anti-CD40/IL-15 combination. CONCLUSION: These studies support the initiation of a clinical trial in patients with cancer utilizing IL-15 in association with the checkpoint inhibitor, anti-PD-1, and intratumoral optimized anti-CD40.
Author Info: (1) National Institutes of Health, Bethesda, Maryland, United States. (2) Transponics, Essex Junction, VT, United States. (3) Frederick National Laboratory for Cancer Research, Fre
Author Info: (1) National Institutes of Health, Bethesda, Maryland, United States. (2) Transponics, Essex Junction, VT, United States. (3) Frederick National Laboratory for Cancer Research, Frederick, MD, United States. (4) National Institutes of Health, Bethesda, MD, United States.
