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Novel CAR-T cells targeting TRKB for the treatment of solid cancer

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Abstract

Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating blood cancers such as B-cell malignancies, however, its effectiveness as an approach to treat solid tumors remains to be further explored. Here, we focused on the development of CAR-T cell therapies targeting tropomyosin-related kinase receptor B (TRKB), a highly expressed protein that is significantly associated with tumor progression, malignancy, and drug resistance in multiple forms of aggressive solid tumors. To achieve this, we screened brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NTF4) ligand-based CAR-T cells for their efficiency in targeting the TRKB receptor in the context of solid tumors, particularly hepatocellular carcinoma and pancreatic cancer. We demonstrated that TRKB is overexpressed not only in hepatocellular carcinoma and pancreatic carcinoma cell lines but also in cancer stem-like cells (CSCs). Notably, BDNF-CAR T and NTF4-CAR T cells could not only effectively target and kill TRKB-expressing pan-cancer cell lines in a dose-dependent manner but also effectively kill CSCs. We also performed in vivo studies to show that NTF4-CAR T cells have a better potential to inhibit the tumor growth of hepatocellular carcinoma xenografts in mice, compared with BDNF-CAR T cells. Taken together, our findings suggest that CAR-T targeting TRKB may be a promising approach for developing novel therapies to treat solid cancers.

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Data availability

All data and materials for this study are available from the respective authors upon reasonable request.

Abbreviations

TRKB:

Tropomyosin-related kinase receptor B

TRK:

Tropomyosin-related kinase

BDNF:

Brain-derived neurotrophic factor

NTF4:

Neurotrophin 4

CSCs:

Cancer stem-like cells

CAR-T:

Chimeric antigen receptor T

NTKR2:

Neurotrophic tyrosine kinase receptor 2

scFv:

Single-chain fragment variable

NTD:

Non-transduced T cells

CRS:

Cytokine release syndrome

ICANS:

Cell-associated neurotoxicity syndrome

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Acknowledgements

We gratefully acknowledge for the technical assistance of Core Facility of West China Hospital (Li Chai, Yi Li and Xing Xu), Histology and Imaging Platform, Core Facility of West China Hospital (Yaping Wu). Manuscript editor Julian Heng (Remotely Consulting, Australia) provided professional English-language editing of this article (Manuscript Certificate No. 0Vb8Nn5I).

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82103107 to B Sun), National Natural Science Foundation of China (Grant No. 82172701 to X Zhao), and 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. ZYYC20002 to X Zhao).

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Author notes

  1. Dandan Liang, Jie Tang have contributed equally to this work.

Authors and Affiliations

  1. Department of Targeting Therapy & Immunology and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Dandan Liang, Jie Tang, Bin Sun, Shuai He, Dong Yang, Haiyan Ma, Yuncang Yun, Yongjie Zhu, Wenwen Wei & Xudong Zhao

  2. Laboratory of Metabolism and Aging Research, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Haiyang Chen

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  1. Dandan Liang
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Contributions

DL and JT have contributed equally to this work. All authors contributed to the conception and design of this study. The experiments were carried out by DL and JT. JT, DL, BS, and DY wrote the original article. SH, HM, YY, and WW analyzed the data. HC and XZ critically revised the article. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Haiyang Chen or Xudong Zhao.

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Ethical approval

Animal experiments in this study were approved by the Animal Ethics Committee of West China Hospital, Sichuan University (ID: 20211492A).

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Liang, D., Tang, J., Sun, B. et al. Novel CAR-T cells targeting TRKB for the treatment of solid cancer. Apoptosis (2024). https://doi.org/10.1007/s10495-024-01936-7

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