Function and evolution of the prototypic CD28ζ and 4-1BBζ chimeric antigen receptors

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T cells targeting CD19 demonstrate significant efficacy in refractory B-cell malignancies.
• Approved CD19 CAR T-cell therapies utilize either CD28/CD3ζ or 4-1BB/CD3ζ signaling domains.
• Despite comparable overall efficacy and safety, these CAR designs confer distinct functional properties to engineered T cells.

Purpose of the Study:

• To review the biological properties of foundational CD19 CAR T-cell prototypes.
• To examine the recent advancements in optimizing CD28- and 4-1BB-based CD19 CAR T cells.
• To discuss strategies for enhancing CAR T-cell function and persistence.

Main Methods:

• Review of existing literature on CD19 CAR T-cell therapy.
• Analysis of the functional differences conferred by CD28 and 4-1BB costimulatory domains.
• Examination of recent research on CAR T-cell engineering and optimization.

Main Results:

• CD19 CAR T cells have achieved remarkable clinical success in B-cell malignancies.
• CD28 and 4-1BB costimulatory domains lead to differential T-cell activation and function.
• Current research focuses on refining existing CD19 CAR designs for improved persistence and reduced exhaustion.

Conclusions:

• Foundational CD19 CAR T-cell designs remain central to current therapies.
• Ongoing research aims to enhance CAR T-cell performance through modulation of signaling domains and T-cell biology.
• Optimizing CAR T-cell function is crucial for sustained clinical benefit in B-cell malignancies.