Reprogramming Immune-Desert Tumors via Triple-Modality Immunotherapy

Cold tumors lack T cells and therefore can resist most immunotherapies in general, including anti-PD-1 inhibitors. We describe a new strategy to change the phenotype from "cold" tumors to "hot" tumors that can be recognized and attacked by the immune system. We will utilize a spatiotemporal cascade model called "Ignite–Release–Reinforce". Using an intratumoral route of administration, the oncolytic virus will produce pyroptosis in the tumor, along with the release of tumor antigens. Then, the systemic delivery of an anti-PD-1 monoclonal antibody will allow effector T cells to perform their designed function. Finally, the use of human induced pluripotent stem cell-derived chimeric antigen receptor T (iPSC-derived CAR-T) cells will provide lasting cytotoxicity. To validate this innovative concept, we will utilize mouse models of glioblastoma and pancreatic cancer and will have 8 groups to assess the effects of each treatment with mono-, dual-, and triple-therapy administration. Outcomes will include tumor burden, T cell infiltrate and cytokine profiles, and survival. We anticipate that the proposed triple-modality therapy will provide the greatest degree of tumor regression and benefit in terms of survival when compared to the other groups. We expect that the triple-therapy will increase the amount of CD8+ T cell infiltrate by 3-5-fold compared to the control and single-agent treated groups, cause greater elimination of regulatory T cells, and induce higher levels of pro-inflammatory cytokines such as IFN-γ, IL-1β, and CXCL10. Pyroptosis markers and antigen presentation capability are anticipated to be the highest in the triple therapy group, leading to the development of a highly inflammatory tumor microenvironment. We hope that our proposed triple-modality therapy may fundamentally change the treatment of immune-desert tumors by converting their tumor microenvironments to more inflammatory environments and leading to greater efficacy and durability of future immunotherapy treatments for patients.