Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Chimeric antigen receptor (CAR)-T cell therapy efficacy relies on T cell persistence and function.
• Distinct CD4+ and CD8+ T cell phenotypes may arise from different CAR intracellular signaling domains (ICDs).

Purpose of the Study:

• To investigate the impact of different CAR ICDs on T cell persistence and effector function.
• To evaluate the efficacy of novel CAR constructs incorporating ICOS and 4-1BB ICDs in solid tumor models.

Main Methods:

• Generation of CAR-expressing T cells with various ICDs (ICOS, CD28, 4-1BB).
• Assessment of CAR T cell persistence and effector function in vivo.
• Evaluation of anti-tumor efficacy in solid tumor models.

Main Results:

• The ICOS ICD significantly enhanced CAR CD4+ T cell persistence, indirectly boosting CAR CD8+ T cell persistence.
• Third-generation CARs combining ICOS and 4-1BB ICDs demonstrated superior anti-tumor effects and in vivo persistence.
• The membrane-proximal ICD position was dominant in third-generation CARs, with ICOS proximal to the membrane yielding optimal benefits.

Conclusions:

• CAR T cell persistence and anti-tumor efficacy can be modulated by specific ICDs.
• Combining ICOS and 4-1BB ICDs, particularly with ICOS proximal to the membrane, represents a promising strategy for enhancing CAR T cell therapy in solid tumors.