CAR-T Cell Therapy
CAR-T cell therapy engineers patient T cells with chimeric antigen receptors that recognize and kill tumor cells with high specificity.
## Overview
Chimeric antigen receptor T-cell (CAR-T) therapy is a form of adoptive cell therapy in which a patient's T cells are genetically modified to express a synthetic receptor that combines antigen-recognition (typically an scFv antibody fragment) with T-cell signaling domains, enabling direct tumor cell killing independent of MHC presentation.
## CAR Structure
First-generation CARs contained only the CD3ζ signaling domain, providing weak T-cell activation. Second-generation CARs added a co-stimulatory domain (CD28 or 4-1BB), dramatically improving persistence and efficacy. 4-1BB (lentiviral vector, slower expansion, greater persistence) vs. CD28 (gammaretroviral, faster expansion, faster exhaustion) design choices affect clinical behavior.
## Manufacturing Process
1. Leukapheresis collects patient T cells
2. T cells are activated with anti-CD3/CD28 beads
3. Viral transduction introduces the CAR transgene
4. Ex vivo expansion over 10-14 days
5. Quality testing + cryopreservation
6. Patient receives lymphodepleting chemotherapy (fludarabine + cyclophosphamide) to create homeostatic space
7. CAR-T infusion (typically 1 dose)
## Approved Products
- **Tisagenlecleucel (Kymriah)**: Anti-CD19, 4-1BB; approved for relapsed/refractory ALL (pediatric/young adult) and large B-cell lymphoma
- **Axicabtagene ciloleucel (Yescarta)**: Anti-CD19, CD28; approved for r/r large B-cell lymphoma
- **Ciltacabtagene autoleucel (Carvykti)**: Anti-BCMA, 4-1BB; approved for relapsed/refractory multiple myeloma
## Toxicities
**Cytokine release syndrome (CRS)**: T-cell activation releases IL-6, IFN-γ, causing fever, hypotension, hypoxia. Graded 1-4 (Lee criteria). Treatment: tocilizumab (anti-IL-6R) for grade ≥2; corticosteroids for refractory cases.
**Immune effector cell-associated neurotoxicity syndrome (ICANS)**: Encephalopathy, aphasia, seizures, cerebral edema. Managed with corticosteroids; dexamethasone is preferred.
**Prolonged cytopenias and B-cell aplasia**: Anti-CD19 CAR-T causes B-cell aplasia requiring IVIG prophylaxis.
## Key Takeaways
- CAR-T cells recognize tumor antigens via scFv domain without requiring MHC presentation
- Lymphodepleting chemotherapy enhances CAR-T expansion by removing competing lymphocytes
- CRS is managed with tocilizumab; ICANS requires corticosteroids
- 4-1BB costimulation provides more durable T-cell persistence than CD28