In Vivo CAR-T Gene Therapy — Gene Therapy & Genetic Interventions
Direct in vivo generation of CAR-T cells using LNP-delivered mRNA, eliminating need for ex vivo cell manufacturing.
Overview
In vivo CAR-T gene therapy represents a paradigm shift from traditional ex vivo CAR-T manufacturing. Instead of extracting patient T cells, engineering them in a lab, and re-infusing them, LNP-delivered mRNA or AAV vectors directly reprogram T cells in the patient's body. Capstan Therapeutics (acquired by Roche) and Umoja Biopharma are developing this approach. A landmark preclinical study showed that LNP-delivered anti-CD5 CAR mRNA could redirect T cells to eliminate cardiac fibroblasts, reversing heart fibrosis in mice. This approach could dramatically reduce the cost and complexity of CAR-T therapy.
Indications
- Cardiac fibrosis and heart failure (preclinical proof-of-concept)
- Cancer immunotherapy (in vivo CAR generation)
- Autoimmune disease (regulatory CAR-T)
- Senescent cell clearance (anti-uPAR CAR-T)
- Age-related fibrosis across organs
Mechanism of Action
LNPs conjugated with anti-CD5 or anti-CD3 antibodies selectively deliver CAR mRNA to T cells in circulation
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| LNP-CAR mRNA (anti-FAP) | Study-specific | Single or repeated IV infusion | T cell-targeted LNP; anti-fibroblast activation protein |
| LNP-CAR mRNA (anti-uPAR) | Study-specific | Single IV infusion | Senolytic CAR-T targeting uPAR+ senescent cells |
Safety & Contraindications
- Transient CAR expression from mRNA is a safety feature (self-limiting)
- Cytokine release syndrome (CRS) risk exists but may be lower than ex vivo CAR-T
- Off-target T cell activation and tissue damage possible
- LNP biodistribution and off-target cell transduction require characterization
- No FDA-approved in vivo CAR-T therapies
- Rubin et al. (2022) anti-fibrosis CAR-T is preclinical