Abstract A28: A comparison of a DNA-sourced neoantigen vaccine to an RNA-sourced frameshift vaccine in the mouse ovarian cancer model

Abstract

Abstract Development of cancer vaccines is currently focused on using neoantigens arising from mutations in the DNA of tumors. We have proposed, and demonstrated, that errors in RNA processing that create frameshift (FS) neoantigens are also a good source of vaccine components, even in tumors that are DNA mutation poor. Here we directly compare the two vaccine approaches in the mouse ovarian model, ID8. Martin et al. (2016) reported that 7 DNA neoepitopes in the ovarian tumor line (ID8-G7) failed to show any protection when tested individually as peptide vaccines even though the peptides elicited an immune response. We created a pooled peptide vaccine consisting of these 7 neoantigens (NeoAg vax). We compared this vaccine to one composed of 13 RNA-sourced FS neoantigens (FS vax). These FSs had conferred protection when tested in the 4T1 mammary and/or B16 melanoma models. 10 of the FSs arise from mis-transcription thru microsatellites and 3 from mis-splicing of exons. In a prophylactic vaccination protocol, both vaccines induce ~20% extended survival compared to mock controls. The FS vax elicited higher numbers of ELISpots than the ID8 control while the NeoAg vax did not when splenocytes were peptide stimulated. The FS vax and NeoAg vax induced T-cells were only significantly cytotoxic to the ID8 cells if anti-PD-L1/CTLA-4 antibodies were included. In the therapeutic vaccination protocol, both the FS vax and the NeoAg vax conferred extended survival in ~20% of the mice compared to controls. Neither vaccine induced more ELISpots compared to controls using peptides. However, the FS vax did elicit more ELISpots in response to ID8 stimulation and more ID8 cytotoxicity than the NeoAg vax. From this work we first conclude that the DNA-sourced neoantigens that did not protect individually can when pooled. Secondly, and more importantly, the RNA-sourced, FS neoantigens can perform as well as the DNA-sourced neoantigens, at least in this model. This may be important as we have shown that all tumors surveyed to date, in contrast to DNA neoantigens, have abundant RNA-sourced FS neoantigens. Citation Format: Milene Tavares Batista, Sierra Murphy, John Lainson, Lui Shen, Stephen Johnston. A comparison of a DNA-sourced neoantigen vaccine to an RNA-sourced frameshift vaccine in the mouse ovarian cancer model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A28.