Hewitt and Bai et al. used lipid nanoparticles to intratumorally deliver IL-23, IL36γ, and OX40L mRNAs in multiple tumor models, inducing strong antitumor responses, control of both treated and distal tumors, and immunological memory. The effects of treatment were attributed to altered cytokine and chemokine expression in the TME, activation of multiple innate and adaptive immune cells, and immune cell mobilization. Efficacy was dependent on Batf3-dependent DCs and CD8+ T cells. The addition of this therapy to checkpoint blockade overcame resistance and improved outcomes. Human PBMCs showed similar cytokine responses in vitro.
Many solid cancers contain dysfunctional immune microenvironments. Immune system modulators that initiate responses to foreign pathogens could be promising candidates for reigniting productive responses toward tumors. Interleukin-1 (IL-1) and IL-12 cytokine family members cooperate at barrier tissues after microbial invasion, in human inflammatory diseases, and in antitumoral immunity. IL-36gamma, in classic alarmin fashion, acts in damaged tissues, whereas IL-23 centrally coordinates immune responses to danger signals. In this study, direct intratumoral delivery of messenger RNAs (mRNAs) encoding these cytokines produced robust anticancer responses in a broad range of tumor microenvironments. The addition of mRNA encoding the T cell costimulator OX40L increased complete response rates in treated and untreated distal tumors compared to the cytokine mRNAs alone. Mice exhibiting complete responses were subsequently protected from tumor rechallenge. Treatments with these mRNA mixtures induced downstream cytokine and chemokine expression, and also activated multiple dendritic cell (DC) and T cell types. Consistent with this, efficacy was dependent on Batf3-dependent cross-presenting DCs and cytotoxic CD8(+) T cells. IL-23/IL-36gamma/OX40L triplet mRNA mixture triggered substantial immune cell recruitment into tumors, enabling effective tumor destruction irrespective of previous tumoral immune infiltrates. Last, combining triplet mRNA with checkpoint blockade led to efficacy in models otherwise resistant to systemic immune checkpoint inhibition. Human cell studies showed similar cytokine responses to the individual components of this mRNA mixture, suggesting translatability of immunomodulatory activity to human patients.
Author Info: (1) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (2) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (3) Moderna Inc., 200 Technology Square, Cambr
Author Info: (1) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (2) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (3) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (4) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (5) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (6) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (7) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (8) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (9) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (10) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (11) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (12) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (13) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (14) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (15) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (16) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (17) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (18) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (19) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. (20) Moderna Inc., 200 Technology Square, Cambridge, MA 02139, USA. joshua.frederick@modernatx.com.
