Scientific publications

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

Mar 17, 2023 | Magazine: Cell Reports. Medicine

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.

CITATION  Cell Rep Med. 2023 Mar 17;100978.  doi: 10.1016/j.xcrm.2023.100978