Abstract
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 β-catenin signaling. The purpose of this study was to evaluate the ability of β-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 4 T1 TNBC cell line. Humanized BALB/c-Rag2nullIl2rγnullSIRPαNOD (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 4 T1 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 4 T-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.
Highlights
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options
Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated tumor infiltrating lymphocytes (TILs) and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment
RX-5902 was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the Programmed death receptor-1 (PD-1) inhibitor in the 4 T-1 murine TNBC model
Summary
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. In metastatic TNBC, the addition of the PD-L1 inhibitor atezolizumab to chemotherapy with nab-paclitaxel improved progressionfree survival in the intent-to-treat population and the PDL1-positive subset, leading to the FDA-approval of this combination in patients with PD-L1-positive metastatic TNBC [11]. Despite these promising results, the median progression-free survival with combination therapy in the PD-L1-positive subgroup was only 7.5 months, highlighting the critical need to enhance the response to immune checkpoint inhibitors in TNBC and increase the proportion of responding patients and the duration of benefit
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