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Higuchi T , Flies DB , Marjon NA , Mantia-Smaldone G , Ronner L , Gimotty PA , Adams S
CTLA-4 blockade synergizes therapeutically with PARP-inhibition in BRCA1-deficient ovarian cancer
Cancer Immunol Res. 2015 Nov;3(11) :1257-68
PMID: 26138335 PMCID: PMC4984269 URL: http://www.ncbi.nlm.nih.gov/pubmed/26138335
AbstractImmune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA(-) ovarian tumors would be vulnerable to checkpoint blockade. To test this, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP-inhibitor. Correlative studies were performed in vitro using human BRCA1(-) cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP-inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (p<0.0001). The survival benefit of this combination was T cell-mediated and dependent on increases in local IFN-gamma production in the peritoneal tumor environment. Evidence of protective immune memory was observed greater than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP-inhibition in the presence of elevated levels of IFN-gamma in human BRCA1(-) cancer cells supports the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP-inhibition induces protective anti-tumor immunity and significant survival benefit in the BRCA1(-) tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer.
NotesHiguchi, Tomoe Flies, Dallas B Marjon, Nicole A Mantia-Smaldone, Gina Ronner, Lukas Gimotty, Phyllis A Adams, Sarah Cancer Immunol Res. 2015 Jul 2. pii: canimm.0044.2015.