Abstract 1427: IL6 trans-signaling robustly promotes the expansion and antitumor activity of CAR T cells

Chimeric antigen receptor T (CAR T) cell immunotherapy targeting CD19 positive B cells malignancies induces promising clinical remissions. However, the treatments are often accompanied with high levels of IL-6 characterized cytokine release syndrome (CRS). Previous studies had shown that sIL-6R are constitutively present in high concentrations in serum. Therefore, when the level of IL-6 is elevated (above nomogram per ml), sIL-6R combines with IL6 to form the IL-6/sIL-6R complex (trans-signaling). The IL-6 trans-signaling plays important roles in regulating immune responses, cell survival, apoptosis, and proliferation. To our knowledge, comprehensive assessment of the IL-6 signaling in biologic functions of CAR T has not been well addressed. We thus tested whether the IL-6 trans-signaling promotes expansion and anti-tumor activity of CAR T. We found that the levels of serum IL-6 and IL-6/sIL-6R complex were positively correlated with anti-CD19 CAR T cell expansion and anti-leukemia response in patients. To simulate the IL-6 trans-signaling, we next constructed a constitutively expression of Hyper IL-6 (HIL-6) with various CAR T cells. Anti-tumor efficacy of HIL-6-CAR T cells were confirmed in leukemia (anti-CD19) and solid tumors (anti-MUC1 and anit-GPC3 CAR T cells targeting lung cancer and hepatocellular carcinoma, respectively). Our results demonstrate that HIL-6-CAR T cells are more effective for suppressing tumor growth and more persistent in xenograft models. Transcriptomic profiling analysis revealed that the expression of genes that facilitate T-cell migration, early memory differentiation and the IL-6/GP130/STAT3 signaling was upregulated in HIL-6 simulated CAR T cells compared to the ones without HIL-6 overexpression. Because IL-6 trans-signaling activates downstream signaling via GP130, we also generated a novel CAR vector with constituted GP130 activation and demonstrated the CAR T cells were superior in anti-tumor activity with delayed xGVHD in xenograft models of leukemia, lung cancer and liver cancer. Taken together, these results showed that IL-6 trans-signaling can significantly enhanced the expansion anti-tumor activity of CAR T cells via GP130/STAT3 activation and GP130/CAR T may have the potential to promote anti-tumor effects with reduced toxicity in vivo.Keywords: Chimeric antigen receptor T, cytokine release syndrome, IL-6 trans-signaling, GP130Citation Format: Peng Li, Zhiwu Jiang, Rui Liao, Zhaoyang Tang. IL6 trans-signaling robustly promotes the expansion and antitumor activity of CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1427.