Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors

Area of Science:

• Immunotherapy
• Cellular Therapy
• Oncology

Background:

• Chimeric antigen receptor T (CAR-T) cell therapy shows promise for B cell malignancies but has limited efficacy in solid tumors due to intrinsic CAR signaling defects.
• Tonic signaling in antigen-free conditions can lead to exhaustion of traditional CAR-T cells, impacting their effectiveness.

Purpose of the Study:

• To develop a novel chimeric receptor, synthetic T cell receptor (TCR) and antigen receptor (STAR), to improve CAR-T cell efficacy against solid tumors.
• To evaluate the signaling properties, anti-tumor activity, and safety of STAR-T cells compared to traditional CAR-T cells.

Main Methods:

• Constructed a double-chain chimeric receptor (STAR) integrating antibody-based antigen recognition with T cell receptor (TCR) constant regions.
• Assessed STAR-T cell signaling, proliferation, antigen sensitivity, and anti-tumor efficacy in solid tumor models.
• Compared STAR-T cells with traditional 28zCAR-T and BBzCAR-T cells in terms of dysfunction, proliferation, and therapeutic effects.

Main Results:

• STAR-T cells did not induce tonic signaling in antigen-free conditions, reducing exhaustion.
• Upon antigen stimulation, STAR-T cells exhibited strong, sensitive TCR-like signaling, leading to improved proliferation and reduced dysfunction compared to 28zCAR-T cells.
• STAR-T cells demonstrated higher antigen sensitivity and potent anti-tumor effects in solid tumor models, outperforming BBzCAR-T cells and matching 28zCAR-T cells without significant toxicity.

Conclusions:

• STAR-T cells possess favorable features, including native TCR-like signaling, enhanced sensitivity, and reduced dysfunction, making them a promising therapeutic strategy for solid tumors.
• The improved performance of STAR-T cells holds potential for reducing antigen loss-related tumor relapse and providing clinical benefit for patients with refractory solid tumors.