MM cure with CAR T-cell therapy: key challenges and potential solutions
| Primary resistance | Use CAR T-cell therapy in early (preferably the first) treatment line and avoid prior immunotherapy-based mode of action |
| Secondary resistance (here, antigen loss) | No prior therapy against same target antigen Dual antigen targeting |
| Pharmacokinetic: poor CAR T-cell engraftment/persistence | May not be required for all CAR T-cell products Use CAR T-cell therapy in early treatment line (or at least collect T cells early) Select memory/naive T-cell subpopulations Perform genetic engineering with transcription factors that enhance T-cell performance |
| Treatment strategy: sequencing of immunotherapy (mode of action and antigen) | Use CAR T cells before bsAbs Perform whole genome sequencing to determine heterozygous and biallelic loss and quantitative analysis to determine antigen density on MM cells and select the mode of action/product |
| Toxicity: CRS/ICANS/neurologic | Vigilant monitoring and proactive therapy Determine minimal effective CAR T-cell dose required |
| Availability: long vein-to-vein time | Use rapid CAR T-cell manufacturing protocol Fresh-in/fresh-out noncryopreserved CAR T-cell product Implement point-of-care manufacturing |
| Access: limited patient access | Reduce cost, for example, with rapid, virus-free, automated CAR T-cell manufacturing Evaluate alternative reimbursement concepts (performance-based, staggered payments) |
| Primary resistance | Use CAR T-cell therapy in early (preferably the first) treatment line and avoid prior immunotherapy-based mode of action |
| Secondary resistance (here, antigen loss) | No prior therapy against same target antigen Dual antigen targeting |
| Pharmacokinetic: poor CAR T-cell engraftment/persistence | May not be required for all CAR T-cell products Use CAR T-cell therapy in early treatment line (or at least collect T cells early) Select memory/naive T-cell subpopulations Perform genetic engineering with transcription factors that enhance T-cell performance |
| Treatment strategy: sequencing of immunotherapy (mode of action and antigen) | Use CAR T cells before bsAbs Perform whole genome sequencing to determine heterozygous and biallelic loss and quantitative analysis to determine antigen density on MM cells and select the mode of action/product |
| Toxicity: CRS/ICANS/neurologic | Vigilant monitoring and proactive therapy Determine minimal effective CAR T-cell dose required |
| Availability: long vein-to-vein time | Use rapid CAR T-cell manufacturing protocol Fresh-in/fresh-out noncryopreserved CAR T-cell product Implement point-of-care manufacturing |
| Access: limited patient access | Reduce cost, for example, with rapid, virus-free, automated CAR T-cell manufacturing Evaluate alternative reimbursement concepts (performance-based, staggered payments) |