期刊
BIOMATERIALS
卷 281, 期 -, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2021.121334
关键词
Oral metronomic chemotherapy; Tumor microenvironment; Immune checkpoint blockade; Complete response; Immunogenic cell death; Tumor-specific immune memory
资金
- National Research Foundation (NRF) - Korean Government Ministry of Science and ICT [2016M3A9B5941836, 2020R1A2C2015026, 2020R1F1A1069889]
- National Center for Inter-university Research Facilities (NCIRF)
- National Research Foundation of Korea [2020R1F1A1069889, 2016M3A9B5941836, 2020R1A2C2015026] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
In this study, a novel metronomic chemotherapy (MCT) featuring combined oral oxaliplatin (OXA) and pemetrexed (PMX) was investigated for its immune-modulating effects on colon cancer. The results showed that MCT improved tumor antigen presentation, increased functional T cells, and elicited tumor-specific long-term immune memory. When combined with anti-PD-1 therapy, MCT achieved a high rate of complete response and induced a tumor-specific memory response. This study highlights the importance of MCT in activating both innate and adaptive immune cells for the successful treatment of colon cancer.
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 (alpha PD-1) therapy, the tumor volume was suppressed by 97.85 & PLUSMN; 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 alpha PD-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.
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