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CLDN18.2-targeting STAR-T cell therapy for pancreatic cancer: a strategy to minimize gastric off-tumor toxicity compared to CLDN18.2 CAR-T

Oncogene volume 44, pages 2440–2452 (2025)Cite this article

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Abstract

Claudin18 isoform 2 (CLDN18.2), primarily expressed in gastric tissue and upregulated in pancreatic cancer (PC), is a key target for innovative treatments like chimeric antigen receptor T (CAR-T) cell therapy. However, CAR-T’s effectiveness comes with a significant risk of on-target, off-tumor (OTOT) toxicity due to CLDN18.2’s presence in normal gastric mucosa. To address this, we developed CLDN18.2-specific synthetic T cell receptor and antigen receptor T (STAR-T) cells. Our research shows that STAR-T and CAR-T cells have comparable in vitro cytotoxicity, but STAR-T cells cause less gastric damage in vivo despite having weaker antitumor effects than CAR-T cells. Clinical tests with gastroscopes confirmed the gastric safety of STAR-T cell therapy, which effectively controlled the disease. Additionally, incorporating the IL12β p40 subunit into STAR-T cells enhanced their function in both lab and animal studies. This evidence suggests that CLDN18.2 STAR-T cell could be a safer alternative to CAR-T cell therapy for PC, meriting further clinical trials.

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Fig. 1: Generation and cytotoxicity of CLDN18.2 STAR-T and CAR-T cells.
Fig. 2: Antitumor effects of CLDN18.2 STAR-T and CAR-T cells on Panc02-CLDN18.2 cells derived-xenograft NCG mice model.
Fig. 3: Treatment of CLDN18.2 STAR-T cells effectively overcome stomach damage.
Fig. 4: Evaluation of CLDN18.2 STAR-T cell therapy effects.
Fig. 5: The effects of p40 and 4-1BB on CLDN18.2 STAR-T cells antitumor function in vitro.
Fig. 6: CLDN18.2-p40 STAR-T cells exhibit better antitumor efficacy in vivo.
Fig. 7: CLDN18.2-p40 STAR-T cells enhance the T cells infiltration without OTOT toxicity.

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Data availability

The data that support the findings of this study are available on request from the corresponding author, L.Y.

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Funding

This study was supported by National Natural Science Foundation of China (82030076, 82470229), Shenzhen Clinical Research Center of Hematology (LCYSSQ20220823091401002), Sanming Project of Medicine in Shenzhen (SZSM202111004), Shenzhen Key Laboratory Foundation (ZDSYS20200811143757022), Medicine Plus Program of Shenzhen University (000003011601).

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Authors and Affiliations

  1. Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, China

    Wei Zhang, Miao Zeng, Xingyu Ma, Jinghong Chen, Jingqiao Qiao, Ziqian He, Guocheng Zhong & Li Yu

  2. Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen, 518060, China

    Wei Zhang & Miao Zeng

  3. Shenzhen Haoshi Biotechnology Co. Ltd, Shenzhen, 518125, China

    Yisheng Li

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Contributions

WZ and YL conceived and designed the experiments. WZ, MZ and XM performed the experimental work. WZ and MZ wrote the manuscript. WZ, JC and YL revised the manuscript. GZ and LY performed the clinical research. JQ and ZH performed the clinical samples analysis. WZ, MZ, XM and JC contributed to the analysis of experimental data. YL and LY supervised the experiments. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Guocheng Zhong, Yisheng Li or Li Yu.

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The authors declare no competing interests.

Ethics approval

This clinical study was proved by the Ethics Committee of Shenzhen University General Hospital with ethics code KYLLHS-20240104A and conducted according to Helsinki Declaration’s principles. Written informed consent was obtained from each participant before specimen collection. All animal experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Shenzhen University (SYXK(粤)2022-0302), the ethics approval code is IACUC-202400138.

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Zhang, W., Zeng, M., Ma, X. et al. CLDN18.2-targeting STAR-T cell therapy for pancreatic cancer: a strategy to minimize gastric off-tumor toxicity compared to CLDN18.2 CAR-T. Oncogene 44, 2440–2452 (2025). https://doi.org/10.1038/s41388-025-03414-z

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