Enhancing Solid Tumor Immunotherapy: A Multi-Model Strategy Integrating Synapse-Tuned CAR Cells with Oncolytic Virotherapy and Immune Checkpoint Modulation

Abstract

Although past successes have been achieved in chimeric antigen receptor (CAR) T cell therapies in the past decade, especially in the field of hematology, they are not without challenges. CAR T cell therapies are fraught with problems for treating solid tumors such as melanoma, a frequently fatal skin cancer with increasing incidence in multiple regions. In 2020, there were a total of 325,000 new cases and around 57,000 deaths associated with the disease being reported (Saginala et al., 2021). The ineffectiveness of CAR T therapy for treating melanoma and other solid tumors can be attributed in part to the tumor’s immunosuppressive microenvironment, physical barriers, antigen heterogeneity, poor T cell infiltration and dynamic tumor biology. Therefore, in this study we propose an approach aimed at increasing the activation of CAR T cells and help CAR T cells to eliminate melanoma more effectively. Building on recently published work we propose to add a post-synaptic density-95, discs large and zona occuldens (PDZ) binding motif to the C-terminus of the CAR and CAR T cells are preloaded with oncolytic poliovirus. In our proposed system poliovirus would be engineered to express a Cas9 system to target PD-L1 gene and inhibit the expression of PD-L1, a well-known immune checkpoint protein. Overall, with the precise targeted killing of melanoma by poliovirus and enhanced activation of CAR T cells, this combined therapy holds promise to significantly improve the efficacy of solid tumor immunotherapy. This comprehensive approach offers promising directions for the development of more effective treatment strategies and their clinical translation.