Abstract

Chimeric antigen receptor (CAR) T-cell therapy has been widely successful in the treatment of B-cell malignancies, including B-cell lymphoma, mantle cell lymphoma, and multiple myeloma; and three generations of CAR designs have led to effective FDA approved therapeutics. Traditionally, CAR antigen specificity is derived from a monoclonal antibody where the variable heavy (V) and variable light (V) chains are connected by a peptide linker to form a single-chain variable fragment (scFv). While this provides a level of antigen specificity parallel to that of an antibody and has shown great success in the clinic, this design is not universally successful. For instance, issues of stability, immunogenicity, and antigen escape hinder the translational application of some CARs. As an alternative, natural receptor- or ligand-based designs may prove advantageous in some circumstances compared to scFv-based designs. Herein, the advantages and disadvantages of scFv-based and natural receptor- or ligand-based CAR designs are discussed. In addition, several translational aspects of natural receptor- and ligand-based CAR approaches that are being investigated in preclinical and clinical studies will be examined.

MeSH

Receptors, Antigen, Lymphoma, B-Cell, Ligands, Immunotherapy, Cells, Therapeutics, T-Lymphocytes, Lymphoma, Mantle-Cell, B-Lymphocytes, Single-Chain Antibodies, Receptors, Chimeric Antigen

Cited by

• Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy. Proc Natl Acad Sci U S A, 2022
• Construction and characterization of chimeric FcγR T cells for universal T cell therapy. Exp Hematol Oncol, 2025
• Mesothelin-based CAR-T cells exhibit potent antitumor activity against ovarian cancer. J Transl Med, 2024
• Natural killer cells in clinical development as non-engineered, engineered, and combination therapies. J Hematol Oncol, 2022
• Genetic Modification of T Cells for the Immunotherapy of Cancer. Vaccines (Basel), 2022
• Ligand-based targeting of c-kit using engineered γδ T cells as a strategy for treating acute myeloid leukemia. Front Immunol, 2023
• Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers. Mol Ther Oncolytics, 2023
• Targeting BCMA in multiple myeloma: designs, challenges, and future directions. Cancer Immunol Immunother, 2025
• Chimeric antigen receptor T cells march into T cell malignancies. J Cancer Res Clin Oncol, 2023
• Split-design approach enhances the therapeutic efficacy of ligand-based CAR-T cells against multiple B-cell malignancies. Nat Commun, 2024
• Joining Forces for Cancer Treatment: From "TCR versus CAR" to "TCR and CAR". Int J Mol Sci, 2022
• The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance. Nat Commun, 2022
• Racing CARs to veterinary immuno-oncology. Front Vet Sci, 2023