Gp96-Ig/Costimulator Combination Platform Improves T Cell Priming, Enhances Immunity and Memory

Abstract

Abstract The recent excitement in the field of immuno-oncology has been driven largely by the clinical success of checkpoint inhibitors. However, 60–90% of patients are still failing to respond to these therapies. It is widely believed that approaches targeting multiple facets of the immune system, including combinations with checkpoint inhibition and costimulator agonism, will be required to improve patient outcomes. Heat Biologics has developed a next generation T cell activating platform called ComPACT (COMbination Pan-Antigen Cytotoxic Therapy) that incorporates expression of a tumor antigen chaperone (gp96-Ig) and a T cell costimulator (OX40L-Ig) within a single vaccine cell line to effectively prime and boost antigen-specific CD4+ and CD8+ T cells. Furthermore, ComPACT stimulates activation of CD127+KLRG1- memory precursor cells, and lacks the toxic systemic inflammatory cytokine production and proliferation of non-specific CD4+ T cells and Tregs observed with systemic administration of OX40 agonist antibodies. ComPACT also led to high frequencies of IFNγ+, TNFα+, granzyme B+ and IL-2+ antigen-specific CD8+ T cells at both priming and boosting. Here, we have further assessed ImPACT and ComPACT-OX40L in combination with the anti-PD1 checkpoint inhibitor and with expression of an additional cell-secreted T cell costimulator, TL1A-Ig. We show that these treatments synergize effectively to amplify antigen-specific T cells and program a memory response. The combination of ComPACT-OX40L/TL1A with αPD1 or αPD-L1 may therefore translate into an efficacious approach generate long lasting memory in immuno-oncology settings.