Table 3 Exploring Resistance Mechanisms and Strategies in Chimeric Antigen Receptor T-cell Therapy for Hematologic Malignancies
From: Challenges and strategies associated with CAR-T cell therapy in blood malignancies
Classification | Resistance mechanisms | Strategies |
|---|---|---|
T-Cell related factors | •Lack of multi-cytokine producing Cells •Poor quality of donor T cells •Anti-CD19 scFv derived from murine •Inappropriate percentage of CD4 + and CD8 + CAR-T-cells •Nature of the costimulatory | •Early referral and leukapheresis to optimize the quality of T cells •Optimizing CAR-T cell design by incorporating additional co-stimulatory molecules •Using fully human or humanized scFvs instead of murine-derived ones to reduce immunogenicity •CRISPR/Cas9-engineered universal CAR-T cells •Multi-targeted CAR-T cells that target multiple antigens on tumor cells to overcome antigen loss or downregulation •Armored CAR-T cells are engineered to secrete cytokines or other therapeutic agents that enhance their activity in the tumor microenvironment •Combination therapy using CAR-T cells together with other treatments such as checkpoint inhibitors or chemotherapy to augment the immune response |
Tumor Cell-Related Factors | •Tumor Heterogeneity •Antigen loss or down regulation •Lineage switching •Tumor Gene Mutation | |
Tumor Microenvironment Related Factors | •Immunosuppressive chemokine signals and chemotaxis •Immunosuppressive cells such as Treg cells, MDSCs, and TAMs •Metabolic Fuel Deprivation |