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

IRENE OLIVERA; ELIXABET BOLAÑOS; JOSE GONZALEZ-GOMARIZ; SANDRA HERVAS-STUBBS; KARINA V. MARIÑO ; CARLOS LURI-REY; IÑAKI ETXEBERRIA; ASSUNTA CIRELLA; JOSUNE EGEA; JAVIER GLEZ-VAZ; SARAY GARASA; MAITE ALVAREZ; IÑAKI EGUREN1.; SONIA GUEDAN; MIGUEL F. SANMAMED; PEDRO BERRAONDO.; GABRIEL RABINOVICH; ALVARO TEJEIRA; IGNACIO MELLERO

CELL REPORTS MEDICINE

CELL PRESS

Año: 2023

2666-3791

Interleukin-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 generated 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-18BP. These T cell combinations were repeatedly injected together inside mouse tumors. Pmel-1 TCR-transgenic T cells electroporated with scIL-12 or DRIL-18 mRNAs exerted powerful therapeutic effects in local and distant melanoma lesions. These effects were associated with T-cell metabolic fitness, enhanced miR-155 control on immunosuppressive target genes and unique changes in the glycosylation profile of surface proteins, enabling adhesiveness to E-selectin. Efficacy of this immunotherapeutic strategy was recapitulated in cultures of tumor-infiltrating lymphocytes (TILs) and CAR T cells. Thus, IL-12 and IL-18 decoy-resistant mRNA synergize to augment the efficacy of adoptive immunotherapy when transduced into antitumor T cells.