TMIC-50 - Siglec-15 is a new myeloid checkpoint in GBM, whose suppression leads to extremely durable responses with oncolytic therapy.

Zika virus (ZIKV) significantly increases survival in multiple syngeneic glioma mouse models; like other oncolytic therapies, it generates a potent, anti-tumor CD8⁺ T-cell response. Post-ZIKV, we observe a 32-fold increase in myeloid cells in the tumor microenvironment. Siglec-15 is a newly identified myeloid immune checkpoint in cancer, which suppresses T-cell activation; an antibody targeting Siglec-15 is currently in clinical trial for lung cancer. Using immunostaining, for the first time, we report Siglec-15 is expressed on myeloid cells in human GBM specimens. In syngeneic murine models, anti-Siglec-15 alone does not improve survival. However, in combination with ZIKV, anti-Siglec-15 significantly improves survival in the CT2A, SB28, and GL261 models. For example, in the CT2A model, the combination increased long-term survivors (at least 90 days) to 60%, compared to 20% with ZIKV alone and 0% with no treatment. To further confirm the role of Siglec-15, we used Siglec-15 knockout (KO) mice and observed 70% long-term survivor rate in Siglec-15 KO mice treated with ZIKV, compared to 40% in wild-type mice (B/6) with ZIKV. ZIKV treatment in Siglec-15 KO mice led to activation of CD8 T-cells and increased expression of cytotoxic molecules granzyme B and perforin, indicating enhanced anti-tumor activity. Additionally, we detected high levels IFN-gamma and TNF-alpha, further supporting the anti-tumor response. We further improved efficacy by targeting PD-1. This combination resulted in 90% long-term survivors. Moreover, in a model for recurrence, upon contralateral rechallenge with CT2A in long-term survivors, we observed long-term memory T-cell responses, with increased numbers of CD8⁺ T-cells displaying effector and resident memory cell phenotypes, compared to age-matched controls. We obtained similar results with immune-resistant SB28 model. This work suggests that oncolytic therapy combined with blocking myeloid checkpoint Siglec-15, using an agent already in humans, and blocking CD8⁺ T cell checkpoint with anti-PD1, is worthy of study in humans.