Oncolytic viruses (OVs) are effective anti-cancer agents, however their abilities to induce anti-tumor immunity are not yet optimal. Mutanome epitopes are a novel source of tumor antigen formed as a result of mutations within the tumor genome. Within this project we attempted to combine B16F10 mutanome vaccination with OV therapy. We confirmed previous findings that significant immune responses to these epitopes can be generated. Furthermore, we designed and cloned a multi-epitope mutanome construct into MG1 Maraba virus and E1-/E3- deleted type 5 Adenovirus to use for heterologous prime-boost vaccination. While we demonstrated that these viruses induced T-cell responses to one mutanome epitope, we failed to detect responses to the other epitopes. Furthermore there was no effect seen on overall survival. This approach warrants further investigation because coupling mutanome vaccination with OV therapy has the potential to exploit the therapeutic effects of the OV while inducing anti-tumor immunity to tumor-unique antigens.

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Background: The CD19 chimeric antigen receptor (CAR) adoptive T-cell therapy for B-cell leukemia is a promising treatment for relapsed or refractory malignities. The overall response rate of CD19 CAR-T cells in clinical trials was greater than 80% for patients with B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin's lymphoma (NHL). However, CAR-T cell therapy of leukemias and solid tumors has been limited by a lot of factors such as antigen loss of tumor escape variants, reduced proliferation, persistence and tumor-infiltration of CAR-T cells in vivo, immunosuppressive tumor environment, absence of ideal antigens and on-target, off-tumor toxicities. Therefore, new strategies improving the safety and efficacy of CAR-T cells, including further T-cell modification to overcome the immune suppression, are tested. Aims: (i) Bispecific CARs designed to express two antigen-binding domains prevent of antigen escape. (ii) T-cells were genetically modified to express CAR along with an inducible IL-21 gene cassette driven by NFAT-responsive promoter. IL-21 directly enhances CAR-T cell activity and anti-tumor effects. (iii) Applying suicide epitope modification in CAR enables significantly increasing the therapeutic safety of CAR-T cells. Methods: CARs were constructed by using molecular biology...