Immunotherapy

IL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells

Abstract

Chimeric antigen receptor (CAR) T cell therapies lead to high clinical response rates in B cell malignancies, and are under investigation for treatment of solid tumors. While high systemic interleukin- (IL-) 6 levels are associated with clinical cytokine release syndrome (CRS), the role of IL-6 trans-signaling within CAR T-cells has not been reported. We generated CAR T cells that constitutively express hyper IL-6 (HIL-6), a designer cytokine that activates the trans-signaling pathway. HIL-6-expressing CAR T-cells exhibited enhanced proliferation and antitumor efficacy in vitro and in xenograft models. However, HIL-6 CAR T cells caused severe graft-versus-host disease (GVHD). Transcriptomic profiling revealed that HIL-6 stimulation of CAR T cells upregulated genes associated with T cell migration, early memory differentiation, and IL-6/GP130/STAT3 signaling. Since IL-6 trans-signaling acts via surface GP130, we generated CAR T cells expressing a constitutively-active form of GP130 and found these retained improved antitumor activity without signs of GVHD in preclinical models of B-cell leukemia and solid tumors. Taken together, these results show that IL-6 trans-signaling can enhance expansion and antitumor activity of CAR T cells via the GP130/STAT3 pathway, and suggest that expression of GP130 within CAR T cells could lead to improved antitumor efficacy without systemic IL-6 trans-signaling.

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Fig. 1: HIL-6 improves the expansion, survival and cytotoxicity of CAR T cells after stimulation by target cells in vitro.
Fig. 2: CAR19/HIL-6 suppressed growth of leukemia but led to development of GVHD in a dose-dependent fashion.
Fig. 3: Cytotoxicity of HIL-6 CAR T cells against lung cancer and hepatocellular carcinoma in xenograft models.
Fig. 4: CAR T cell treatment with HIL-6 upregulates expression of genes associated with cell migration, memory differentiation, and the IL-6/GP130/STAT3 pathway.
Fig. 5: GP130 signaling leads to improve CAR T cell antitumor efficacy.

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Acknowledgements

This study is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No.XDB19030205, No.XDA1205030; National Natural Science Foundation of China (NSFC), No.81773301, 81700156, 8187012, 81873847; the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2020351); Guangdong Special Support Program, NO.2017TX04R102; the Frontier and key technology innovation special grant from the Department of Science and Technology of Guangdong province, No. 2015B020227003; the Natural Science Fund of Guangdong Province-Doctoral Foundation, No. 2017A030310381; Guangdong Laboratory of Regenerative Medicine and Health-Guangzhou Frontier Exploration Project, No.2018GZR110105003; Science and Technology Planning Project of Guangdong Province, China (2017B030314056); Science and Technology Program of Guangzhou, China (202002020083); Guangzhou Medical University High-level University Construction Research Startup Fund, NO. B195002004013.

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Contribution: PL, ZJ, RL, JL, and YY conceived and designed research; ZJ, RL, JL, XH, SC, SL, YL, QW, SW, SL, PS, PL, and YJ performed experiments, collected, and analyzed data; DW, LQ, RZ designed and constructed the CAR; YL, XD, WW, SC, TZ, PL, DP, YY, RW, YY, and PL wrote the manuscript; and all authors revised and approved the manuscript.

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Correspondence to Yao Yao or Peng Li.

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Jiang, Z., Liao, R., Lv, J. et al. IL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells. Leukemia (2020). https://doi.org/10.1038/s41375-020-01085-1

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