In Vivo CAR-T Cell Engineering: Translating Vector Pharmacology into Therapeutic Performance
TL;DR
A Quality-by-Design (QbD) framework is proposed-a systematic, science- and risk-based development approach that begins with predefined product objectives and links critical quality attributes to material attributes and process controls and discusses development pathways that emphasize platform–indication matching, innate immune evasion, and adjunctive T-cell conditioning to address the persistence gap and safety control.
Abstract
In Vivo CAR-T cell engineering delivers chimeric antigen receptor (CAR) molecules transgenes directly to endogenous T cells using lentiviral vectors or targeted lipid nanoparticles, bypassing the manufacturing processes of ex vivo cellular therapies. Lentiviral vectors provide integration-based expression for sustained tumor control, whereas lipid nanoparticles enable transient, repeat-dosable therapies for autoimmune disease. First-in-human clinical trials have confirmed proof-of-concept: CAR-T cells expand, deplete target cells, and generate clinical responses, including negative minimal residual disease in multiple myeloma and induce B-cell depletion in systemic lupus erythematosus. However, persistence remains substantially shorter than ex vivo CAR T cell products. This review presents platform architecture, preclinical data, and emerging clinical evidence. We propose a Quality-by-Design (QbD) framework-a systematic, science- and risk-based development approach that begins with predefined product objectives and links critical quality attributes to material attributes and process controls- integrating vector pharmacology with immune parameters and discuss development pathways that emphasize platform–indication matching, innate immune evasion, and adjunctive T-cell conditioning to address the persistence gap and safety control.