期刊
BMC CANCER
卷 20, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12885-020-07500-1
关键词
RX-5902; Triple-negative breast cancer; p68; beta-Catenin; PD-1 inhibitor; Immunotherapy; Humanized mouse models
类别
资金
- National Institutes of Health (NIH)
- National Cancer Institute (NCI) [5P30CA046934-25, 1K23CA172691-01A1]
- CPRIT Scholar Award [RR160093]
- Rexahn Pharmaceuticals, Inc.
BackgroundTriple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear beta -catenin signaling. The purpose of this study was to evaluate the ability of beta -catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC.MethodsTreatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4T1 TNBC cell line. Humanized BALB/c-Rag2(null)Il2r gamma (SIRP)-S-null alpha (NOD) (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells.ResultsThe addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p<0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p<0.01).ConclusionsConclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.
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