Comparison of anti-OX40 to PD-1 and CTLA-4 blockade in T cell immunization/priming models (TUM3P.1047)

Abstract

Abstract OX40 agonists have shown to enhance anti-tumor immunity in several mouse tumor models with similar efficacy to PD-1 and CTLA-4 blockade. We wanted to compare these T cell immune enhancing strategies in subcutaneous vaccine models to understand the role that each of these Abs might have in immune priming. We used both the OVA-specific CD4 and CD8 TCR transgenic adoptive transfer models, D011.10 and OT1, to determine the effect these antibodies have upon vaccination with ovalbumin (OVA). Mice were immunized with whole OVA protein in the absence of adjuvant (soluble OVA). The Abs were delivered on the day of immunization and one day later. Peripheral blood and spleens were analyzed at several time points after immunization. We found that the OX40 agonist in both T cell models enhanced the % and numbers of Ag-specific T cells to a greater extent then either CTLA-4 or PD-1 blockade. This was true both early after activation (4 days) as well as survival of T cells 28 days following immunization in both models. Based on this evidence we hypothesize that OX40 agonists may be more important for immune cell priming to tumor Ags and that PD-1 and CTLA-4 blockade may play a role in decreasing T cell tolerance within the tumor microenvironment. Hence these immune activating pathways most likely have non-overlapping pathways to activate T cells and we now have compelling in vivo evidence that combining OX40 agonists with checkpoint inhibitors have synergistic effects in mouse tumor models.