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Membrane-bound TRAIL-armoring augments CAR-T cells in mesothelin-positive solid malignancies

Alessia Volpe1, Juan Zurita1, Larissa Shenker1

  • 1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Journal for Immunotherapy of Cancer
|May 21, 2026
PubMed
Abstract

Insights

Engineered chimeric antigen receptor (CAR)-T cells armored with membrane-bound tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) effectively target tumors with varied antigen expression. This innovative immunotherapy enhances anti-cancer activity and improves survival in preclinical models.

Area of Science:

  • Immunotherapy
  • Oncology
  • Cellular Therapy

Background:

  • Chimeric antigen receptor (CAR)-T cell therapy targeting mesothelin (MSLN) is effective for high-MSLN tumors but limited by heterogeneous antigen expression.
  • An innovative approach involves engineering MSLN-specific (M28z) CAR-T cells to express a membrane-bound (MB)-TRAIL chimera on their surface.
  • This MB-TRAIL armor enhances CAR-T cell anticancer activity, addressing challenges posed by heterogeneous antigen expression in tumors.

Purpose of the Study:

  • To engineer and evaluate MB-TRAIL-armored MSLN-directed M28z CAR-T cells for enhanced anticancer efficacy.
  • To assess the in vitro and in vivo therapeutic potential of this novel CAR-T cell construct against tumors with heterogeneous MSLN expression.
  • To investigate the combination therapy of MB-TRAIL-armored CAR-T cells with doxorubicin for overcoming TRAIL resistance.

Main Methods:

  • Engineered MB-TRAIL-armored MSLN-directed M28z CAR-T cells and assessed in vitro toxicity against MSLN-expressing tumor cells.
  • Utilized triple-multiplex bioluminescence imaging for longitudinal, in vivo assessment of CAR-T cell dynamics and tumor responses in xenograft models (MSTO-211H PM, A549 NSCLC).
  • Evaluated the therapeutic benefit of combining MB-TRAIL-armored CAR-T cells with doxorubicin in an A549 xenograft model.

Main Results:

  • MB-TRAIL M28z CAR-T cell therapy induced apoptosis in both MSLN+ and MSLN- tumors, significantly improving survival in heterogeneous MSTO-211H PM and A549 NSCLC models.
  • The treatment provided sustained protection against metastatic spread in the MSTO-211H model.
  • Doxorubicin combination therapy overcame TRAIL resistance in the A549 model, increasing susceptibility to MB-TRAIL M28z CAR-T cells and reducing metastatic growth.

Conclusions:

  • The MB-TRAIL-armored CAR-T cell strategy demonstrates superior antitumor efficacy compared to standard M28z CAR-T cells by targeting heterogeneous antigen expression.
  • This approach provides a foundation for a new class of clinically translatable TRAIL-armored CAR-T cell immunotherapies.
  • The findings suggest potential for treating a wider range of malignancies with this enhanced CAR-T cell therapy.
Keywords:
Chimeric antigen receptor - CARImmunotherapyLung CancerMesotheliomaSolid tumor

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