Synergy of optimized administration sequence and timing of active DC immunotherapy with a PD1 checkpoint inhibitor in a mouse model of renal cell carcinoma.

31 Background: AGS-003 is an immunotherapy consisting of autologous dendritic cells electroporated with amplified total tumor RNA plus synthetic CD40L RNA and is currently being tested in combination with standard of care to extend survival of newly diagnosed metastatic renal cell carcinoma (RCC) patients in the Phase 3 ADAPT clinical trial. We set out to establish a model system based on the Renca mouse model to more thoroughly study the AGS-003 mechanism of action and identify optimal combination therapies, including with a PD1 checkpoint inhibitor (aPD1 CPI). Methods: Mouse DC precursors were processed in a similar manner to how human monocytes are processed to manufacture AGS-003. Mature DCs were injected s.c. to treat BALB/c mice in an orthotopic syngeneic RCC model. This model system was utilized to test the efficacy and mechanism of action of the AGS-003-like homologous mouse DCs in combination with a murine monoclonal antibody PD1 CPI (anti-mPD1). Results: Murine DCs with similar properties to AGS-003 in combination with anti-mPD1 and sunitinib, resulted in recruitment and migration of lymphocytes into the tumor microenvironment and an increase in peripheral blood CD8+CD28+CD45RA- memory T cells in vivo. Multiple combination dosing strategies were tested and only one dosing regimen (DCs administered prophylactically followed by aPD1 mAb administered therapeutically) showed a substantial synergistic effect (67 days median OS) while all other DC/aPD1 dosing combinations did not exceed the efficacy of DC monotherapy treatment (44.5-48 days median OS). Control animals treated with PBS had a median OS of 29 days. Conclusions: These data demonstrate the importance of the administration sequence for active immunotherapy and aPD1 CPI combination therapy. Our data suggest that the cellular immune response must be initiated and established prior to administration of the aPD1 CPI/sunitinib combination therapy in order to observe synergy in this RCC mouse model. This model may be useful to explore additional combination therapies and effective treatment regimens with other therapeutic agents to guide future clinical development.