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• W4324348529 abstract "Checkpoint blockade immunotherapy is a potent class of cancer treatment, however, the complex immunosuppressive tumor microenvironment (TME) often requires multi-agent combinations to be effective. Current cancer immunotherapy combination approaches are cumbersome, usually involving one-drug-at-a-time scheme. Here, we devise Multiplex Universal Combinatorial Immunotherapy via Gene-silencing (MUCIG), as a versatile approach for combinatorial cancer immunotherapy. We harness CRISPR-Cas13d to efficiently target multiple endogenous immunosuppressive genes on demand, allowing us to silence various combinations of multiple immunosuppressive factors in the TME. Intratumoral AAV-mediated administration of MUCIG (AAV-MUCIG) elicits significant anti-tumor activity with several Cas13d gRNA compositions. TME target expression analysis driven optimization led to a simplified off-the-shelf MUCIG targeting a four gene combination (PGGC: Pdl1, Galectin9, Galectin3 and Cd47 ). AAV-PGGC shows significant in vivo efficacy in syngeneic tumor models. Single cell and flow profiling revealed that AAV-PGGC remodeled the TME by increasing CD8 + T cell infiltration and reducing myeloid-derived immunosuppressive cells (MDSCs). MUCIG thus serves as a universal method to silence multiple immune genes in vivo, and can be delivered via AAV as a therapeutic approach." @default.
• W4324348529 created "2023-03-16" @default.
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• W4324348529 date "2023-03-15" @default.
• W4324348529 modified "2023-09-27" @default.
• W4324348529 title "Multiplexed inhibition of immunosuppressive genes with Cas13d for on-demand combinatorial cancer immunotherapy" @default.
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• W4324348529 doi "https://doi.org/10.1101/2023.03.14.532668" @default.
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