EXTH-22. TARGETING A NEWLY DISCOVERED IMMUNE CHECKPOINT, SIGLEC-15, INCREASES ONCOLYTIC EFFICACY OF ZIKA VIRUS (ZIKV) IN GLIOBLASTOMA (GBM)

Abstract

Abstract We are developing ZIKV as a therapy for GBM. We previously demonstrated ZIKV specifically kills GBM stem cells. Using GL261 and CT2A mouse models, ZIKV induces a CD8+ T-cell mediated anti-tumor response and leads to 65% and 40% long term survivors, respectively (0%-untreated controls). ZIKV treatment significantly increases the number of myeloid cells in the tumor microenvironment (with about 10,000 infiltrating macrophages per ZIKV-treated brain, 1,000 cells per untreated brain). We hypothesized that by targeting a myeloid immune checkpoint, we would further enhance efficacy. Siglec-15 is a newly described myeloid checkpoint, and anti-siglec-15 antibody is currently in clinical trial for patients with advanced or metastatic solid tumors (NCT03665285). While there was no effect of anti-siglec-15 treatment alone, we observed increased efficacy when combined with ZIKV (cure rate: GL261-70%, CT2A-60% with ZIKV+anti-siglec-15 antibody; GL261-20%, CT2A-0% with anti-siglec-15 antibody alone; GL261-30%, CT2A-25% ZIKV alone; GL261-0%, CT2A-0% without treatment). Since recurrence is a major problem, we performed re-challenge experiments in cured mice at 6 months. Mice previously treated with anti-siglec-15 antibody and ZIKV had 70% long-term survival, compared to 30% of age matched untreated controls. This supports our earlier findings that an immunological response after ZIKV engenders long-term, tumor-specific, immune surveillance. Lastly, we used Siglec-15 knockout mice to confirm our observations. After treating Siglec-15 knockout mice bearing CT2A tumors with ZIKV, 70% animals were cured. There was no significant difference in survival between CT2A-bearing Siglec-15 knockout mice without ZIKV treatment compared to CT2A-bearing wild type hosts. Taken together, our work suggests targeting putative myeloid suppressor cells, combined with oncolytic ZIKV and its ensuing anti-cancer stem cell and activated CD8+ T-cell effects, may be an effective tool in neuro-oncology. Targeting Siglec-15 may also enhance other oncolytic or cytotoxic therapies.