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  3. Bruton tyrosine kinase inhibitors preserve anti-CD19 chimeric antigen receptor T-cell functionality and reprogram tumor micro-environment in B-cell lymphoma

Bruton tyrosine kinase inhibitors preserve anti-CD19 chimeric antigen receptor T-cell functionality and reprogram tumor micro-environment in B-cell lymphoma

  • Cytotherapy. 2023 Apr 17;S1465-3249(23)00066-X. doi: 10.1016/j.jcyt.2023.03.005.
Wenjing Luo 1,  Chenggong Li 1,  Jianghua Wu 1,  Lu Tang 1,  Xindi Wang 1,  Yinqiang Zhang 1,  Zhuolin Wu 1,  Zhongpei Huang 1,  Jia Xu 1,  Yun Kang 1,  Wei Xiong 2,  Jun Deng 3,  Yu Hu 4,  Heng Mei 5
Affiliations

Affiliations

  • 1 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China.
  • 3 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China.
  • 4 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: dr_huyu@126.com.
  • 5 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: hmei@hust.edu.cn.
PMID: 37074239 DOI: 10.1016/j.jcyt.2023.03.005
Abstract

Background aims: Combination therapy is being actively explored to improve the efficacy and safety of anti-CD19 chimeric antigen receptor T-cell (CART19) therapy, among which Bruton tyrosine kinase inhibitors (BTKIs) are highly expected. BTKIs may modulate T-cell function and remodel the tumor micro-environment (TME), but the exact mechanisms involved and the steps required to transform different BTKIs into clinical applications need further investigation.

Methods: We examined the impacts of BTKIs on T-cell and CART19 phenotype and functionality in vitro and further explored the mechanisms. We evaluated the efficacy and safety of CART19 concurrent with BTKIs in vitro and in vivo. Moreover, we investigated the effects of BTKIs on TME in a syngeneic lymphoma model.

Results: Here we identified that the three BTKIs, ibrutinib, zanubrutinib and orelabrutinib, attenuated CART19 exhaustion mediated by tonic signaling, T-cell receptor (TCR) activation and antigen stimulation. Mechanistically, BTKIs markedly suppressed CD3-ζ phosphorylation of both chimeric antigen receptor and TCR and downregulated the expression of genes associated with T-cell activation signaling pathways. Moreover, BTKIs decreased interleukin 6 and tumor necrosis factor alpha release in vitro and in vivo. In a syngeneic lymphoma model, BTKIs reprogrammed macrophages to the M1 subtype and polarized T helper (Th) cells toward the Th1 subtype.

Conclusions: Our data revealed that BTKIs preserved T-cell and CART19 functionality under persistent antigen exposure and further demonstrated that BTKI administration was a potential strategy for mitigating cytokine release syndrome after CART19 treatment. Our study lays the experimental foundation for the rational application of BTKIs combined with CART19 in clinical practice.

Keywords

BTK inhibitors; CART19; T-cell exhaustion; lymphoma; tumor micro-environment.

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