Synergistic anticancer activity of a novel oral chemotherapeutic agent containing trifluridine and tipiracil in combination with anti-PD-1 blockade in microsatellite stable-type murine colorectal cancer cells

摘要

Trifluridine/tipiracil (FTD/TPI) is a combination of FTD, an antineoplastic thymidine-based nucleoside analog, and TPI, which acts to enhance the bioavailability of FTD in vivo. It is used to treat patients with unresectable advanced or recurrent colorectal cancer that is refractory to standard therapies. We investigated the anticancer activity of FTD/TPI combined with anti-mouse programed cell death 1 (PD-1) monoclonal antibody (mAb) against CMT-93 cells, which are microsatellite stable (MSS)-type murine colorectal cancer cells. Tumor growth inhibition (TGI) after treatment with anti-mouse PD-1 mAb monotherapy (0.1 mg, i.p., days 1, 5, 9) and FTD/TPI monotherapy (150 mg/kg/day, p.o., days 1-14) were 86.7% and 52.7%, respectively, and that of the combination was 98.4%. The TGI of the combination therapy was significantly greater than that of each monotherapy (P<0.05). The combination therapy caused complete tumor regression in four out of five mice without body-weight reduction, but neither of the monotherapies resulted in complete tumor regression. Low dose FTD/TPI (75 and 100 mg/kg) combined with anti-mouse PD-1 mAb also showed significant antitumor activity against CMT-93 tumors. Flow cytometric analysis revealed that a higher CD8+ T cell ratio among total lymphocytes and a lower regulatory T cells (Tregs) ratio in CD4+ T cells in the combination group compared with that in the control group. These results suggested that the combination therapy induced a cytotoxic response from infiltrated cytotoxic CD8+ T cells and reduced immunosuppressive activity as indicated by decreased Tregs. In this study, the combination therapy was found to have synergistically greater antitumor activity against CMT-93 cells. These preclinical findings indicated that FTD/TPI and anti-mouse PD-1 mAb combination therapy may be a promising treatment option, even for MSS-type colorectal cancer.