Abstract 469: Progress towards developing a universal, prophylactic cancer vaccine.
Authors: Shen Luhui, Hojoon Lee, Kathryn Sykes, Stephen Albert Johnston
Journal: Cancer Research (2013)

Abstract Background: Our goal is to create a vaccine that would be administered to prevent cancer. Such a vaccine would overcome many of the problems and limitations in current cancer treatments by eradicating the tumor at the earliest stages, before evasion strategies or metastasis could evolve. We have chosen to compose the vaccine of frameshift (FS) peptides, which can be produced by various mutations and abnormal splicings in tumors. These peptides would be novel to the immune system and produce strong immune responses. We have conducted bioinformatics and genetics analyses to identify a list of aberrant RNA that encode FS peptides and their frequency in different tumors. Previous studies showed a mis-splicing FS RNA of SMC1A is common in different human and mouse tumors. Vaccination with the SMCA1 FS peptide protected against tumor progression in the B16 mouse melanoma model and several mouse mammary gland tumor models, both injectable and transgenic. A key aspect of this strategy is the ability to pool FS components to provide broad protection against any tumor that could arise. Here we test the ability to pool antigens using mouse tumor models. Results: Besides SMC1A FS, we identified potential FS peptides encoded in human and mouse tumors for SLAIN2 FS, RBM14 FS and THAP2 FS RNA. These were tested individually in the BALB-NeuT transgenic mouse mammary tumor model. Each demonstrated the ability to delay tumor progression. However, when all four antigens were pooled into a vaccine, the protection was no better than each individual component. ELISA analysis of each FS peptide indicated that the humoral immune responses to SMC1AFS, SLAIN2FS, and RBM14FS in the pooled vaccine were reduced while the THAP2FS humoral immune was low in both the individual and pooled response. This suggested that THAP2FS could suppress the immune response to the other components. To test this, a composite vaccine excluding THAP2FS was tested. This vaccine produced robust, additive protection. Discussion: We conclude that though THAP2FS was itself protective, it suppressed the response to the other antigens in a pooled vaccine. As we administered the gene vaccine, each cell received all four components. Therefore, we speculate that THAP2 dominates antigen presentation in a cell. This implies that each component of the prophylactic vaccine will need to be tested for its ability to be pooled. This screen has now been added to the process. Future Plans: The ability to pool antigens was the last hurdle in the pre-clinical development of the prophylactic vaccine. ∼30% of the possible human vaccine components also are in mouse tumors, so these can be directly tested for the ability to be pooled. We are also developing a chip to test for human immune response to these tumor antigens in cancer patients. With these advances we should be able to propose a vaccine for a Phase I safety trial. (This research is supported by an Innovation Award from the DoD and The Keck Foundation to SAJ.) Citation Format: Shen Luhui, Hojoon Lee, Kathryn Sykes, Stephen Albert Johnston. Progress towards developing a universal, prophylactic cancer vaccine. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 469. doi:10.1158/1538-7445.AM2013-469