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CAR-γδ T Cells Targeting Claudin18.2 Show Superior Cytotoxicity Against Solid Tumor Compared to Traditional CAR-αβ T

Yueqi Zhao1, Yinghui Li1, Shuaiqi Wang1

  • 1Department of Immunology, CAMS Key Laboratory T-Cell and Cancer Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing 100005, China.

Cancers
|March 28, 2025
PubMed
Abstract

Insights

This study developed universal Chimeric Antigen Receptor Gamma Delta (CAR-γδ) T cells targeting Claudin18.2 (CLDN18.2) for solid tumor treatment. These CAR-γδ T cells demonstrated potent anti-tumor activity in preclinical models, offering a promising new immunotherapy strategy.

Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • Claudin18.2 (CLDN18.2) is a tumor-associated antigen highly expressed in gastric cancer and other solid tumors.
  • Current CAR-T cell therapies targeting CLDN18.2 are limited by MHC-dependent antigen recognition.
  • Gamma Delta (γδ) T cells offer MHC-independent cytotoxicity and are ideal for universal CAR-T cell development.

Purpose of the Study:

  • To construct and evaluate novel universal CAR-γδ T cells targeting CLDN18.2.
  • To assess the in vitro and in vivo efficacy of these CAR-γδ T cells against CLDN18.2-positive solid tumors.

Main Methods:

  • Construction of CAR-CLDN18.2-γδ T cells via lentiviral infection.
  • Assessment of CAR expression and lentivirus titer.
  • In vitro cytotoxicity assays against CLDN18.2-positive cancer cells.
  • In vivo anti-tumor efficacy studies in tumor-bearing NSG mice.

Main Results:

  • Successful construction and characterization of CAR-CLDN18.2-γδ T cells.
  • CAR-γδ T cells exhibited specific cytotoxicity and cytokine secretion (Granzyme-B, Perforin-1, IFN-γ) against CLDN18.2-positive cells.
  • CAR-γδ T cells demonstrated superior cytotoxicity compared to CAR-αβ T cells in vitro.
  • Significant tumor growth inhibition and prolonged survival observed in vivo.

Conclusions:

  • Universal CAR-CLDN18.2-γδ T cells are a promising therapeutic strategy for CLDN18.2-positive solid tumors.
  • This approach offers potential for developing more universal CAR-γδ T-cell-based tumor immunotherapies.
Keywords:
CLDN18.2immunotherapyuniversal CAR-T cellγδ T cell

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