mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy
Irene Olivera 1 , Elixabet Bolaños 1 , Jose Gonzalez-Gomariz 1 , Sandra Hervas-Stubbs 1 , Karina V Mariño 2 , Carlos Luri-Rey 1 , Iñaki Etxeberria 1 , Assunta Cirella 1 , Josune Egea 1 , Javier Glez-Vaz 1 , Saray Garasa 3 , Maite Alvarez 3 , Iñaki Eguren-Santamaria 1 , Sonia Guedan 4 , Miguel F Sanmamed 3 , Pedro Berraondo 3 , Gabriel A Rabinovich 5 , Alvaro Teijeira 1 , Ignacio Melero 6
Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their systemic therapeutic efficacy when delivered intratumorally.
Here, we mix T cells engineered with mRNAs to express either single-chain IL-12 (scIL-12) or an IL-18 decoy-resistant variant (DRIL18) that is not functionally hampered by IL-18 binding protein (IL-18BP). These mRNA-engineered T cell mixtures are repeatedly injected into mouse tumors. Pmel-1 T cell receptor (TCR)-transgenic T cells electroporated with scIL-12 or DRIL18 mRNAs exert powerful therapeutic effects in local and distant melanoma lesions.
These effects are associated with T cell metabolic fitness, enhanced miR-155 control on immunosuppressive target genes, enhanced expression of various cytokines, and changes in the glycosylation profile of surface proteins, enabling adhesiveness to E-selectin.
Efficacy of this intratumoral immunotherapeutic strategy is recapitulated in cultures of tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells on IL-12 and DRIL18 mRNA electroporation.
CITA DEL ARTÍCULO Cell Rep Med. 2023 Mar 17;100978. doi: 10.1016/j.xcrm.2023.100978