Driving CARs with alternative navigation tools - the potential of engineered binding scaffolds

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Chimeric antigen receptor (CAR) T-cell therapies show promise against B-cell malignancies.
• Limitations exist for CAR T-cells targeting other antigens, including issues with scFv binding domains causing tonic signaling and T-cell exhaustion.

Purpose of the Study:

• To discuss the advantages and disadvantages of engineered binding scaffolds as alternatives to scFvs in CAR T-cell design.
• To review studies evaluating non-antibody-based scaffolds for CAR T-cell applications.

Main Methods:

• Review of recent studies on engineered binding scaffolds, natural ligands, and receptors for CAR T-cell therapy.
• Critical discussion of immunogenicity risks associated with engineered scaffolds.

Main Results:

• Engineered binding scaffolds, natural ligands, and receptors can efficiently mediate antigen recognition for CAR T-cells.
• Non-immunoglobulin-based scaffolds can replace scFvs, mitigating issues like tonic signaling and T-cell exhaustion.
• The immunogenicity of engineered scaffolds is comparable to humanized scFvs.

Conclusions:

• Engineered binding scaffolds and natural ligands/receptors are viable alternatives to scFvs for CAR T-cell design.
• These alternatives offer potential for improved CAR T-cell efficacy and broader therapeutic applications.
• Future CAR T-cell designs are expected to increasingly utilize engineered binding scaffolds and natural ligands/receptors.