147 (PB027) - Combination Therapy with Poly-gamma-glutamic Acid and Anti-PD-1 Results in Synergistic Therapeutic Effects against Cancers

Abstract

Background: Combinatorial therapeutic strategies based on innate immunity have the potential to enhance the treatment efficacy of cancer therapies. We have been demonstrated that poly-γ-glutamic acid (γ-PGA) has a potent innate immune modulating activities including natural killer cell activation and interferon secretion through Toll-like receptor 4 and may be a useful mean for immunotherapeutic as reported previously. The programmed death protein 1 (PD-1) plays a critical part in downregulating immune responses and limiting immunogenic response in T cells. Here, we report the anti-cancer effects of γ-PGA combined with PD-1 blockade in murine colon adenocarcinoma and murine melanoma. Material and methods: It was performed to evaluate the in vivo combinatorial anti-cancer effects by oral administration of γ-PGA and intraperitoneal injection of anti-PD-1 in C57BL/6N mice transplanted with MC38 cell, a colorectal cancer cell. And the another study was carried out to examine the synergetic therapeutic efficacy by γ-PGA and anti-PD-1 against B16F10 melanoma tumor model in mice. Results: Combination therapy with γ-PGA and anti-PD-1 produced significantly longer tumor growth delay than other treatment and almost completely inhibited melanoma tumor growth, and also the improved longterm survival rate was shown compared to γ-PGA or anti-PD-1 alone. Similar experiment was performed in melanoma tumor and the result shows that co-treatment with γ-PGA and anti-PD-1 significantly prolonged survival rate compared with anti-PD-1 alone in MC38 tumor model and dramatically reduced MC38 tumor growth but had no synergistic effect. The results showed that the survival rate of the combinatorial treatment was superior to anti-PD-1 alone. Conclusions: Based on the resistance mechanism of PD-1 blockade with low response rates in many patients, γ-PGA treatment having an innate immune modulating activity combined with anti-PD-1 can induce stronger anti-tumor immunity and destroy the target cancer cells. In this study, oral administration of γ-PGA with intraperitoneal injection of anti-PD-1 dramatically inhibited tumor growth and enhanced the survival rate in MC38 and B16F10 tumor-bearing mice. The study demonstrates that the tumor microenvironment was controlled by administration of γ-PGA, thus results in exertion of immune checkpoint inhibitor. These data provide a strong preclinical evidence for a novel combinatorial therapeutic strategy that can be assessed in prospective clinical trials. No conflict of interest.