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.

journal_name

Leukemia

journal_title

Leukemia

authors

Jiang Z,Liao R,Lv J,Li S,Zheng D,Qin L,Wu D,Chen S,Long Y,Wu Q,Wang S,Lin S,Huang X,Tang Z,Shi P,Zhou H,Liu Q,Zhao R,Li Y,Jie Y,Wei W,Lai P,Du X,Cui S,Weinkove R,Liu P,Pei D,Yao Y,Li P

doi

10.1038/s41375-020-01085-1

subject

Has Abstract

pub_date

2020-11-09 00:00:00

eissn

0887-6924

issn

1476-5551

pii

10.1038/s41375-020-01085-1

pub_type

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