The rational combination of metronomic chemotherapy (MCT) with immunotherapy has the potential of immune modulation inducing enhancement of host immunity, thereby overcome tumor induced immunosuppressive defense. In this study, oral formulation of oxaliplatin (OXA) and pemetrexed (PMX) were developed by complexing ionically with Nα-deoxycholyl-l-lysyl-methylester (DCK) as intestinal permeability enhancer to form OXA/DCK-NE and PMX/DCK-OP respectively. OXA/DCK-NE and PMX/DCK-OP were combined for oral MCT and its anti-tumor effect was examined against maximum tolerated dose (MTD) of same drug combination by intravenous administration in colon cancer (CT26) syngeneic mouse model. MCT was able to modulate immunity in CT26 mouse model compared to MTD, such as enhancement of effector T-cell population in tumor, elevation of tumor antigen uptake, and activation of dendritic cells as analyzed by flow cytometry of tumor tissue and draining lymph nodes (TDLN). Moreover, cytotoxic T-cell and helper T-cell populations in lymphoid organs such as blood, spleen, and TDLN were found to be upregulated in MCT group but not in MTD group. Furthermore, on combining MCT with αPD-1, the tumor suppression was more effective showing 97.8% decrease in tumor volume compared to that of control leading to tumor free mice (95% complete response). Mice that achieved complete antitumor response upon re-challenge, demonstrated that combination therapy of MCT and αPD-1 induced memory response which was further confirmed by 1.5-fold enhanced antigen specific memory response compared to αPD-1 only treated group as detected by secretion of INF-γ.
In this study, we observed that combination of OXA/DCK-NE and PMX/DCK-OP with αPD-1 therapy synergized immunomodulatory effect by enhancing the populations of effector T-cells thereby inducing complete response and antigen specific memory response. Thus, this suggests the rationality of combination treatment with oral metronomic OXA and PMX with αPD-1 to elicit effective immune modulation.
Citation Format: Ruby Maharjan. Metronomic treatment of orally available oxaliplatin and pemetrexed to potentiate the efficacy of anti-PD-1 by modulating tumor immunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6693.