Abstract 5565: Skin-targeted combinatorial DNA immunization overcomes tumor resistance to PD1 therapy

Despite the remarkable treatment benefits associated with interventional checkpoint blockade for solid tumors, many patients ultimately progress on therapy. The development of novel strategies that can overcome resistance to checkpoint therapy remains a considerable unmet clinical need. In this context, we developed a novel tumor immunization strategy that is multifunctional and combines co-delivery of plasmid DNA encoding antigen and molecules driving immunostimulatory function and antigen targeting. Specifically, we targeted expression of plasmid DNA encoding the stress response transcription factor XBP1 and the melanoma-associated antigen TRP2 fused to heat shock protein HSP70. Transient skin-localized expression promotes a pro-immunogenic skin microenvironment and the induction, recruitment, and maintenance of Type-1 cytotoxic CD8 T cells (Tc1), including Tc1 T-cell infiltrates within the tumor microenvironment (TME), and tumor regression in a PD1-resistant mouse melanoma model. These data suggest a novel therapeutic strategy in which combined effects of localized XBP1 and HSP70 antigen conjugation establishes a PD1-responsive TME for effective and durable treatment of PD1-resistant cancers. Citation Format: Louis D. Falo. Skin-targeted combinatorial DNA immunization overcomes tumor resistance to PD1 therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5565.