Targeting Carbonic Anhydrase IX augments immune checkpoint blockade to enhance anti-tumor immunity, reduce metastasis and extend survival
Shawn C. Chafe1,*, Paul C. McDonald1, Oksana Nemirovsky1, Michael Lyle2, Shoukat Dedhar1
1Department of Integrative Oncology, BC Cancer Research Centre, Vancouver, BC, Canada; 2Welichem Biotech Inc., Burnaby, BC, Canada
While treatment strategies involving immune checkpoint blockade have significantly improved survival for certain patients across a broad spectrum of advanced solid cancers, many patients fail to respond. Hypoxia is a common feature of the tumor microenvironment (TME) that contributes to immune suppression and limits the efficacy of immunotherapy, suggesting the need for innovative combinatorial therapeutic approaches that improve and widen treatment response. Tumor cells adapt to hypoxia by upregulating Carbonic Anhydrase IX (CAIX), a cell surface metabolic regulator of tumor pH that drives acidosis and facilitates mobilization of myeloid-derived suppressor cells, processes that inhibit anti-tumor immunity and promote metastasis. Here, we have evaluated the potential therapeutic benefit of targeting CAIX in combination with immune checkpoint inhibitors in preclinical models of metastatic breast cancer and melanoma. Treatment of mice bearing B16F10 melanoma tumors with SLC-0111, a clinically evaluated small molecule inhibitor of CAIX, in combination with anti-PD-1 and anti-CTLA-4 antibodies reduced tumor growth and provided a survival benefit, compared to the checkpoint inhibitors alone. Similar results were observed upon treatment with SLC-0111 in combination with anti-PD-1 and anti-4-1BB antibodies. Furthermore, treatment of mice bearing orthotopic 4T1 breast tumors with SLC-0111 in combination with anti-PD-1 and/or anti-CTLA-4 antibodies significantly reduced metastatic burden compared to immunotherapy alone. These effects were associated with differential leukocyte infiltration. These data suggest that targeting CAIX in the TME in combination with immune checkpoint blockade is a potential therapeutic strategy for enhancing response and survival in patients with hypoxic solid malignancies.
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