mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy

• DOI: 10.1016/j.xcrm.2023.100978
• Publication Date: 2023-03-18T00:22:54Z
• Authors: Irene Olivera; Elixabet Bolaños; Jose Gonzalez-Gom...; Sandra Hervas-Stubbs; Karina V. Mariño; Carlos Luri-Rey; Iñaki Etxeberria; Assunta Cirella; Josune Egea; Javier Glez-Vaz; Saray Garasa; Maite Alvarez; Iñaki Eguren-Sant...; Sonia Guedan; Miguel F. Sanmamed; Pedro Berraondo; Gabriel A. Rabino...; Alvaro Teijeira; Ignacio Melero
• Keywords: Decoy; Adoptive immunotherapy; Adoptive Cell Transfer; Cancer Immunotherapy

Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previously reported that transient engineering tumor-specific CD8 cells with IL-12 mRNA enhanced their systemic efficacy when delivered intratumorally. Here, we mix engineered mRNAs to express either single-chain (scIL-12) or an IL-18 decoy-resistant variant (DRIL18) is not functionally hampered by binding protein (IL-18BP). These mRNA-engineered mixtures are repeatedly injected into mouse tumors. Pmel-1 receptor (TCR)-transgenic electroporated scIL-12 DRIL18 exert powerful effects in local and distant melanoma lesions. associated metabolic fitness, miR-155 control on immunosuppressive target genes, expression various cytokines, changes glycosylation profile surface proteins, enabling adhesiveness E-selectin. Efficacy this intratumoral immunotherapeutic strategy recapitulated cultures tumor-infiltrating lymphocytes (TILs) chimeric antigen (CAR) electroporation.