Increased Il-27 Is Associated With Poor Prognosis In Renal Cell Carcinoma And Supports Use Of Srf388, A First-In-Class Il-27p28 Blocking Antibody, To Counteract Il-27-Mediated Immunosuppression In This Setting

IL-27 is a heterodimeric member of the IL-12/IL-23 cytokine family that consists of two subunits, IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), and binds to a heterodimeric receptor composed of the IL-27 receptor subunit alpha (IL-27RA) and glycoprotein 130 (gp130). IL-27 signals through the JAK-STAT pathway to limit the duration and intensity of T cell-mediated immunity by altering immunoregulatory receptor expression and proinflammatory cytokine secretion during infection and cancer. Analysis of data from The Cancer Genome Atlas (TCGA) revealed that IL-27p28, EBI3, and IL-27RA transcript levels are often elevated in tumors from patients with renal cell carcinoma (RCC) and that high levels of these genes are associated with poor clinical outcome. Using an IL-27 gene signature derived from activated CD4+T cells, several genes downstream of IL-27 signaling were found to be coordinately regulated in a subset of RCC patients and associated with poor prognosis. Moreover, plasma levels of the EBI3 subunit of IL-27 were found to be elevated in a subset of RCC patients and inversely correlated with both disease-free and overall survival. The ability of IL-27 to dampen immune responses and the association of elevated levels of this cytokine with poor clinical outcome in RCC suggest that IL-27 blockade may represent a promising strategy to treat cancer in patients with high circulating EBI3. SRF388 is a first-in-class IL-27p28 antibody that blocks the interaction of IL-27 with IL-27RA and inhibits IL-27 signaling in primary human immune cells. This mechanism results in diminished inhibitory receptor expression and increased cytokine production. Exogenous IL-27 inhibited the activity of PD-1 blockade in vitro by counteracting the increased cytokine production observed after treatment of activated human PBMCs from healthy donors and RCC patients. Furthermore, treatment with SRF388 stimulated increased cytokine production in activated PBMCs from patients with RCC in the absence of exogenous IL-27; this proinflammatory response was further enhanced when combined with PD-1 blockade. Finally, SRF388 demonstrated single-agent anti-tumor activity in a murine orthotopic model of RCC. These data indicate that blockade of IL-27 can potentiate anti-tumor responses by counteracting IL-27-mediated immune escape and may represent a promising strategy for treating cancer patients. Citation Format: Matthew Rausch, Jing Hua, Devapregasan Moodley, Kerry F. White, Katherine H. Walsh, Christine E. Miller, Gege Tan, Benjamin H. Lee, Isabelle Cousineau, Jean-Baptiste Lattouf, John Stagg, Vito J. Palombella, Pamela M. Holland, Jonathan A. Hill. Increased IL-27 is associated with poor prognosis in renal cell carcinoma and supports use of SRF388, a first-in-class IL-27p28 blocking antibody, to counteract IL-27-mediated immunosuppression in this setting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4550.