Cancer vaccine in combination with radiopharmaceutical therapy (RPT) upregulates type I interferon pathway in Ovalbumin-expressing tumor model 2254330

Abstract

Abstract Introduction To enhance the efficacy of therapeutic cancer vaccines, combination strategies are needed to overcome mechanisms of immunoresistance. RPT, such as pan-cancer targeting 90Y-NM600, can act as an immunomodulating agent. We have previously found that cancer vaccines administered prior to RPT elicited greater anti-tumor response in murine models than if administered after RPT. Here, we investigated the mechanisms by which combination treatment of vaccine prior to RPT enhanced antitumor immunity using an ovalbumin-expressing tumor model. Methods 1x106 E.G7-OVA-PD-L1hi tumor cells were subcutaneously implanted in C57Bl/6 mice. 0.5x106 naïve OT-I CD8+ T cells were transferred to the tumor-bearing mice (day -3), followed by vaccination with OVA-encoding DNA plasmid (day -2), and low dose 90Y-NM600 injection (delivering 5Gy to the tumor; day 0). Tumors were collected 7- and 14-days post-RPT for transcriptomic analysis and flow cytometry. In a follow up study, mice were similarly treated, and concurrently treated or not with a STING antagonist H-151, and followed for changes in tumor growth. Results Combining tumor vaccine with RPT significantly upregulated genes associated with type I interferon pathway along with increased cytotoxic and CD8+ T cell scores. This finding aligned with increased infiltration of SIINFEKL-specific CD8+ T cells 7 days post-RPT. Genes associated with cytotoxicity significantly decreased 14 days post-RPT. Addition of H-151 did not affect tumor growth. Conclusion RPT enhanced the infiltration and functional activity of vaccine-activated tumor-specific CD8+ T cells, likely through STING-independent type I interferon signaling. Funding Source T32 CA009135 F31CA305954 P01 CA250972 Topic Categories Vaccines and Immunotherapy (VAC)