2. Academic Validation
  3. BCL-2 mutant B7H6-CAR-T cells synergized with venetoclax for treating small cell lung cancer

BCL-2 mutant B7H6-CAR-T cells synergized with venetoclax for treating small cell lung cancer

  • J Immunother Cancer. 2025 May 7;13(5):e010073. doi: 10.1136/jitc-2024-010073.
Huihui Zhang # 1 2,  Liliang Xia # 1,  Wendi Xuzhang 1,  Ziming Li 1,  Junshi Zhang 2,  Fanlin Li 2,  Chen Cheng 2,  Jiawen Wang 2,  Xincheng Zong 3,  Xuanming Yang 4 2 5 6,  Shun Lu 4
Affiliations

Affiliations

  • 1 Shanghai Lung Cancer Center, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Faculty of Art & Science, University of Toronto, Toronto, Ontario, Canada.
  • 4 Shanghai Lung Cancer Center, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China shunlu@sjtu.edu.cn xuanmingyang@sjtu.edu.cn.
  • 5 Joint International Research Laboratory of Metabolic and Developmental Sciences, Shanghai Jiao Tong University, Shanghai, China.
  • 6 Department of Gynaecology and Obstetrics, Shanghai Pudong New Area people's Hospital, Shanghai, China.
  • # Contributed equally.
PMID: 40341023 DOI: 10.1136/jitc-2024-010073
Abstract

Background: Patients with small cell lung Cancer (SCLC) generally have a poor prognosis, with an exceptionally high proliferative rate and a strong propensity for early metastasis, indicating the urgent need for novel therapies. The development of chimeric antigen receptor (CAR)s targeting solid tumors is limited owing to the lack of target antigens and low efficacy. In this study, we aimed to discover new targets for SCLC CAR-T therapy and develop CAR-T-based combinational treatment against SCLC in preclinical models.

Methods: The in vitro antitumor activity of B7H6-specific CAR-T cell was evaluated. Venetoclax-resistant B7H6 CAR-T cell were designed and the synergistic effect of venetoclax and B7-H6 CAR-T cells was tested in vitro and in vivo.

Result: B7H6 is highly expressed in SCLC tumors. CAR-T cell against B7H6 displayed antigen-specific antitumor efficacy. Bcl-2(D103E)-expressing CAR-T cells showed resistance to venetoclax-induced Apoptosis. The combinational treatment of venetoclax and Bcl-2(D103E)-expressing B7H6-targeting showed potent anti-SCLC effect in vitro and in vivo.

Conclusions: Our findings suggest that the combination of Bcl-2 mutant-expressing B7H6-targeting CAR-T cells and venetoclax could be a promising novel strategy against B7H6-expressing SCLCs and Other solid tumors, providing the foundation for CAR-T cells and proapoptotic small molecules therapy in patients with SCLCs in a clinical trial.

Keywords

Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Immunotherapy; Lung Cancer; Solid tumor.

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