TRAIL-R1-Targeted CAR-T Cells Exhibit Dual Antitumor Efficacy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) is highly expressed on various tumors but minimally on normal tissues.
• This differential expression makes TRAIL-R1 an attractive target for cancer immunotherapy.

Purpose of the Study:

• To develop and characterize chimeric antigen receptor (CAR) T cells targeting TRAIL-R1 for cancer treatment.
• To evaluate the efficacy and mechanisms of action of TR1⁴¹⁹ CAR-T cells against TRAIL-R1-positive tumors.

Main Methods:

• Utilized a single-chain variable fragment (scFv) from a previously identified TRAIL-R1-targeting antibody (TR1⁴¹⁹) to engineer CAR-T cells.
• Characterized the phenotypes and functions of third-generation TR1⁴¹⁹-28BBζ CAR-T cells, including target sensitivity, proliferation, and PD-1 expression.
• Assessed the ability of CAR-T cells to induce tumor cell death through death receptor-dependent apoptosis and T-cell-mediated cytotoxicity.

Main Results:

• Third-generation TR1⁴¹⁹-28BBζ CAR-T cells demonstrated enhanced target sensitivity and proliferative capacity.
• Slightly increased PD-1 expression was observed on CAR-T cells post-antigen stimulation.
• TR1⁴¹⁹ CAR-T cells effectively induced TRAIL-R1-positive tumor cell death via a dual mechanism.

Conclusions:

• TR1⁴¹⁹ CAR-T cells represent a promising therapeutic strategy for targeting TRAIL-R1-positive malignancies.
• The dual mechanism of action enhances the potential of these CAR-T cells in cancer immunotherapy.