Parallel 4-1BB Signaling in Dual DLL3/CD56-Targeting CAR-T Cells Triggers Adaptive Proliferation and Functional...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR)-T cell therapy faces challenges in solid tumors due to limited persistence and proliferation.
• DLL3 is a promising target for small cell lung cancer (SCLC) therapy.

Purpose of the Study:

• To develop an enhanced CAR-T cell strategy for solid tumors.
• To improve the efficacy and durability of CAR-T cell therapy in preclinical SCLC models.

Main Methods:

• Engineered DLL3-targeting CAR-T cells (DBBζ.CBB) co-expressing CD56 CSR and incorporating parallel 4-1BB costimulatory signaling.
• Preclinical evaluation in SCLC models.
• Combination therapy with DLL3 trispecific T-cell engagers (TriTCE).

Main Results:

• DBBζ.CBB demonstrated sustained tumor infiltration, prolonged persistence, and superior antitumor activity in SCLC models.
• Parallel 4-1BB signaling dynamically programmed T cell fate, promoting expansion, memory maintenance, and delaying exhaustion.
• Combination therapy synergistically enhanced tumor eradication, boosted T cell infiltration and activation, and mitigated exhaustion.

Conclusions:

• The engineered DBBζ.CBB CAR-T cells effectively overcome limitations of current CAR-T therapies in solid tumors.
• The combinatorial framework of DBBζ.CBB and TriTCE offers a promising strategy for enhancing CAR-T cell efficacy and durability.
• This approach is clinically translatable for solid tumor treatment.