Abstract
Group 3 medulloblastomas (MB) harboring MYC gene amplification are generally considered a relative immune desert. This is despite often carrying a relatively high mutational burden, which is associated with immune checkpoint inhibitor sensitivity in other cancers. For this reason the use of checkpoint inhibitors has largely been dismissed as a potential treatment strategy in these high risk tumors. However, our work using TGFb receptor small molecule inhibitors (TGFbRi) in MYC-amplified MB has shown that inhibiting the TGFb pathway results in increased antigen presenting machinery and checkpoint ligands. And while TGFb pathway inhibition alone significantly prolongs survival in MB-bearing mice, it was not curative with all animals eventually dying of disease. Therefore, we set out to exploit the tumor intrinsic and extrinsic changes that occur in MB with TGFb pathway inhibition and hypothesized that combining TGFb pathway inhibition with immune checkpoint inhibition would result in meaningful improvements in rates of survival. Indeed, “priming” MBs with a TGFbRi in conjunction with weekly administration of OX40 agonist resulted in tumor rejection and durable overall survival relative to either therapy alone. Intracranial tumors collected at various time points throughout TGFbRi “priming” showed increased cell surface expression of OX40, PD-L1 and MHC class one molecules within 1–2 days of TGFbRi treatment. Concurrently, there was a consistent increase in CD4+ and CD8+ T cells into the tumor, which was potentiated with OX40 agonism. These findings imply that the sequence of TGFb receptor inhibition followed by OX40 agonism could be a potent, synergistic combination that should be actively explored in upcoming clinical trials.
LOW GRADE GLIOMA