Oncolytic virotherapy: An alternative immune based strategy leveraging cancer testis antigens in synovial sarcoma
Synovial sarcoma (SS) is an aggressive cancer that disproportionately affects young adults. The ability to target immune checkpoints has contributed to the overall decline in predicted cancer mortality rates. However patients with SS have failed to derive benefit from this approach on clinical trials to date. This has been attributed to its less robust immune environment as compared with more immunotherapy responsive cancers. SS is one of several cancers that overexpresses cancer testis antigens CTAs). Leveraging this approach through vaccine-based approaches has similarly not proven fruitful. Engineered T-cells targeting the CTAs appear promising, but still yield responses in under half the patients. Furthermore, this modality is limited to a narrow subset of patients with the disease. Our preliminary studies have shown that SS cell lines are susceptible to infection with engineered oncolytic measles viruses (MV) built on the Edmonston vaccine backbone. In particular one such virus encoding the immune stimulant neutrophil activating protein (NAP) is not only able to kill these SS lines, but also induce an immunogenic cell death. We offer an alternative approach to exploiting the CTAs in SS. By utilizing reverse engineering to incorporate CTAs into our viral construct we believe we can take full advantage of the immune boosting potential seen in our MV-s-NAP in SS. This proposal seeks to generate and demonstrate the preliminary efficacy of two novel oncolytic measles virus strains incorporating widely expressed, but less studied CTAs, paving the way for future translational studies. In addition to their direct killing effect, these constructs may have the potential to: increase the relevance of immune checkpoint inhibitors in synovial sarcoma and augment the efficacy of the ongoing adoptive T-cell therapies in this deadly disease.