Local immunotherapy ideally stimulates immune responses against tumors while avoiding
toxicities associated with systemic administration. Current strategies for tumor-targeted,
gene-based delivery, however, are limited by adverse effects such as off-targeting
or antivector immunity. We investigated the intratumoral administration of saline-formulated
messenger (m)RNA encoding four cytokines that were identified as mediators of tumor
regression across different tumor models: interleukin-12 (IL-12) single chain, interferon-alpha
(IFN-alpha), granulocyte-macrophage colony-stimulating factor, and IL-15 sushi. Effective
antitumor activity of these cytokines relied on multiple immune cell populations and
was accompanied by intratumoral IFN-gamma induction, systemic antigen-specific T cell
expansion, increased granzyme B+ T cell infiltration, and formation of immune memory.
Antitumor activity extended beyond the treated lesions and inhibited growth of distant
tumors and disseminated tumors. Combining the mRNAs with immunomodulatory antibodies
enhanced antitumor responses in both injected and uninjected tumors, thus improving
survival and tumor regression. Consequently, clinical testing of this cytokine-encoding
mRNA mixture is now underway.
