Abstract 1098: Combination of a DNA vaccine-induced immune checkpoint blockade and radiation therapy induces anti-tumor immunity

Abstract Background: Immune checkpoint blockade (ICB) immunotherapy improves survival for many cancer patients, but those with immunologically ‘cold’ tumors do not derive benefit. Radiation therapy (RT) has been demonstrated to augment antitumor immunity in preclinical and clinical studies and may enhance response to ICB in immunologically cold tumors. We have developed DNA-based, cost-effective, and versatile ICB immunotherapies. Here, we test the use of these alone and in combination with RT as a novel treatment approach in syngeneic murine melanoma models. Materials and methods: We constructed ICB DNA vaccines targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1), CTLA-4 Vax and PD-1 Vax, respectively. These were delivered to mice by intramuscular or intratumoral electroporation. The effects of combinations of ICB DNA vaccines and RT were monitored for generation of endogenous anti-CTLA-4 and anti-PD-1 antibodies, modification of tumor microenvironment (TME), and tumor response in mice bearing syngeneic B78 or B16 melanoma. Results: Intramuscular vaccination with CTLA-4 Vax and PD-1 Vax induced endogenous anti-CTLA-4 and anti-PD-1 antibodies, respectively, and the titers increased with additional vaccinations. Vaccination with CTLA-4 Vax and PD-1 Vax alone or in combination (Dual Vax) did not inhibit the murine B16 melanoma model; however, the combination of CTLA-4 Vax and RT (CTLA-4 Vax + RT) led to enhanced infiltration of the TME with effector T cells. Dual Vax combined with RT enabled systemic anti-tumor immunity in mice bearing two B16 melanoma tumors in which only one was radiated. With intra-tumoral route of vaccination, the Dual Vax + RT treatment induced a trend toward systemic anti-tumor response in the immunologically cold B78 tumor model. Conclusions: DNA vaccines that stimulate endogenous production of antibodies against immune checkpoints may serve as an alternative form of ICB. The combination of ICB DNA vaccine and RT enabled anti-tumor immunity and tumor response in preclinical models of melanoma. Citation Format: Keng-Hsueh Lan, Ying-Chun Sheng, Keng-Li Lan, KyungMann Kim, Sung-Hsin Kuo, Zachary Morris. Combination of a DNA vaccine-induced immune checkpoint blockade and radiation therapy induces anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1098.