Using oral oxaliplatin and pemetrexed formulations with improved bioavailability, Maharjan and Choi et al. showed that immunogenic death of a colon carcinoma line was induced better by metronomic (MCT) than maximum tolerated dosing, with less immuno- and overall toxicity. MCT dosing more effectively boosted tumor cell MHC expression, tumor sensitivity to cytotoxic T cells, activation of and antigen presentation by DCs in tumor-dLNs, numbers of PD-1- and proliferating TILs, IFNγ expression by tumor-specific TILs and splenocytes, macrophage migration to LNs, and polarization to M1 TAMs in tumor-bearing mice. MCT combined with anti-PD-1 eradicated tumors and induced specific memory.
Contributed by Paula Hochman
ABSTRACT: In this study, we investigated the immune-modulating effects of a novel metronomic chemotherapy (MCT) featuring combined oral oxaliplatin (OXA) and pemetrexed (PMX) for colon cancer. OXA and PMX were ionically complexed with lysine derivative of deoxycholic acid (DCK), and incorporated into nanoemulsions or colloidal dispersions, yielding OXA/DCK-NE and PMX/DCK-OP, respectively, to improve their oral bioavailabilities. MCT was not associated with significant lymphotoxicity whereas the maximum tolerated dose (MTD) afforded systemic immunosuppression. MCT was associated with more immunogenic cell death and tumor cell MHC-class I expression than was MTD. MCT improved the tumor antigen presentation of dendritic cells and increased the number of functional T cells in the tumor. MCT also helped to enhance antigen-specific memory responses both locally and systemically. By combining MCT with anti-programmed cell death protein-1 (αPD-1) therapy, the tumor volume was suppressed by 97.85 ± 84.88% compared to the control, resulting in a 95% complete response rate. Upon re-challenge, all tumor-free mice rejected secondary tumors, indicating the induction of a tumor specific memory response. Thus, MCT using an OXA and PMX combination, together with αPD-1, successfully treated colon cancer by activating both innate and adaptive immune cells and elicited tumor-specific long-term immune memory while avoiding toxicity caused by MTD treatment.
Author Info: (1) Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. (2) Research Institute of Pharmaceutical Science
Author Info: (1) Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. (2) Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea. (3) Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea. (4) College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, 58554, Republic of Korea. (5) Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, 5 Hwarang-ro 140gil, Seongbuk-gu, Seoul, 02792, Republic of Korea. (6) Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. (7) Global R&D Center, IcureBNP, Seoul, 07985, Republic of Korea. (8) College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, 58554, Republic of Korea; Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam, 58554, Republic of Korea. Electronic address: jwpark@mokpo.ac.kr. (9) Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address: yrbyun@snu.ac.kr.
