Cellular Immunogenicity Assessments in CAR-T Cell Therapies: Current Insights and Future Directions.

CAR-T-cells can drive MHC class-I-mediated CD8 + cytotoxic T-cell response towards CAR constructs in addition to an antibody response. Immune response may also develop towards residuals present in the CAR-T cell product such as AAV, CRISPR/CAS9, and expamers. Health authorities recommend developing assays to assess both humoral and cellular immunogenicity towards the CAR-T protein. For the assessment of a humoral response, scientists can leverage the guidance and experience from anti-drug antibody (ADA) assays being developed for biologics. However, measuring CAR-T induced cellular immune responses may be challenging due to factors like cell survival, assay variability, lack of relevant positive controls, reagents, etc. This commentary overviews the strategy for investigating cellular immunogenicity for CAR-T products in development, describing the process for risk assessment, guidance on sample collection, including logistics of cell processing and handling, and design of CAR domain related peptides to elicit the memory response from dosed subjects. The experience gained from cellular immunogenicity assessments implemented for ongoing CAR-T-cell therapies and challenges encountered are presented with concrete recommendations, without disclosure of proprietary data. The clinical relevance/impact of assessing cellular immunogenicity for CAR-T therapies and any association with humoral response will also be delineated.