Abstract PO049: Enhancement of anticancer efficacy of PD1 blockade by combining with a polysaccharide PG2 isolated from Huang Qi

Abstract

Abstract Over the past few years, immune checkpoint blockade therapies have gained FDA approval for the treatment of a variety of tumor types. However, only a fraction of patients within each given cancer type benefited from these treatments. Strategies to improve the anticancer efficacy of immune-checkpoint blockade will be important. Here we investigated whether a botanical drug PG2 which has been approved by Taiwan FDA for relieving cancer related fatigue may enhance the anti-cancer efficacy of PD-1 blockade. PG2 is a mixture of polysaccharide purified from Astragalus membranaceus, an elite herb that is most frequently used in the traditional chinese medicine. PG2 has been shown to enhance proliferation of umbilical cord-derived mesenchymal stem cells and modulate immune responses. However, whether PG2 displays any anticancer or immune modulating activity remains unclear. In this study, we incubated mouse splenocytes with PG2 at 0.5 mg/mL in vitro and collected culture supernatant to determine cytokine/chemokine by Luminex. We found PG2 increased production of interferon-γ (54.2 ± 31.1 vs. 22 ± 7.6 pg/mL, p = 0.001), interleukin-10 (35.2 ± 8.1 vs. 4.9 ± 0.9 pg/mL, p = 0.0007), macrophage inflammatory protein 1 alpha (MIP1a, 849 ± 137.5 vs. 352.6 ± 44.5 pg/mL, p = 0.004), and MIP1b (1670 ± 235.9 vs. 646.2 ± 112.1 pg/mL, p = 0.004) when compared to vehicle control. The anticancer effect of PG2 was assessed on mouse models of breast cancer 4T1 and colon cancer CT26. Although PG2 alone given weekly x 4 had no anticancer effect on 4T1-bearing mice, the percentage of CD8+ T cells (6 ± 2.6% vs. 1.7 ± 0.6%, p = 0.03) and the PD1+CD8+ T cells (4.9 ± 2.3 vs. 1.2 ± 0.3, p = 0.04) were significantly increased in tumor microenvironment of PG2-treated mice compared to control mice. Importantly, combining PG2 with anti-PD1 weekly x 4 significantly prolonged the median survival of 4T1-bearing mice to 50.5 days, as compared to 42.5 days of PBS control (p = 0.007), PG2 alone (47.5 days, p = 0.02), or anti-PD1 alone (45 days, p = 0.004). Treatment of CT26-bearing mice with the combination of PG2 and anti-PD1 also increased the median survival from 53 days of control mice, 49 days of PG2 alone, or 54 days of anti-PD-1 alone to 64 days of PG2 + anti-PD1 (p < 0.0001 for all comparisons). Flow cytometry analysis showed that the number of MDSCs in spleen was significantly reduced in CT-26-bearing mice treated with PG2 + anti-PD1 (53.8 ± 8.4 × 105) compared to control (137.5 ± 7.7 × 105, p = 0.02) or anti-PD1-treated groups (261.1 ± 51.8 × 105, p < 0.0001). Interestingly, treatment of PG2 elevated the expression of NKG2D on splenocytes in CT-26-bearing mice (19 ± 1.7% vs. control 11.1 ± 3.2%, p = 0.02). Taken together, the anticancer efficacy of anti-PD1 therapy was dramatically improved when combined with PG2. These results provide strong rationales and preclinical evidence for the development of clinical trials of combining anti-PD-1 with PG2 in cancer patients. Such therapeutic strategy may not only improve anti-cancer efficacy but also alleviate cancer associated fatigue syndrome. Citation Format: Jung-Tung Hung, Jing-Rong Huang, Shih-Pin Chiou, Fei-Yun Lo, Jing-An Cheng, Alice L. Yu. Enhancement of anticancer efficacy of PD1 blockade by combining with a polysaccharide PG2 isolated from Huang Qi [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO049.