Beyond Viability: Functional Attrition and In-Use Stability Challenges in CAR-T Cell Therapies - 04/11/26

Highlights |
• | Functional potency declines earlier and more extensively than membrane viability during the CAR-T in-use period. |
• | Cytokine secretion and cytotoxicity are more sensitive indicators of post-thaw quality loss than viability assays. |
• | Device and material interfaces contribute to adsorption, shear stress, leachables exposure, and functional attrition. |
• | Approved CAR-T products exhibit substantial heterogeneity in beyond-use dating, thawing procedures, and handling requirements. |
• | A multi-attribute, risk-based framework is proposed for CAR-T in-use stability assessment and regulatory validation. |
Abstract |
Chimeric antigen receptor T-cell (CAR-T) therapies are living medicines whose quality can change during the interval between thawing and infusion. This review addresses a clinically important gap: product release and beyond-use dating remain largely viability-centred, although functional potency may deteriorate earlier under thermal, mechanical, oxidative, and material-associated stress. This review proposes a conceptual framework that treats in-use quality as the outcome of interacting product, handling, device, operational, and patient-related determinants, and uses this framework to integrate evidence from commercial products, investigational programs, device compatibility studies, and regulatory documents. The evidence indicates that membrane viability is an incomplete surrogate for the delivered functional dose: CAR expression, cytotoxicity, and cytokine secretion can decline at different rates and may be impaired while viability remains within nominal acceptance limits. The review further shows that product labels differ substantially in thawing procedures, storage conditions, administration devices, and beyond-use windows, creating operational and regulatory challenges for treatment centres and multinational development programs. By linking mechanism, measurable quality attributes, clinical workflow, and regulatory validation, this review advances a multi-attribute, risk-stratified approach to in-use stability assessment. The framework provides a basis for designing potency-sensitive validation studies, improving handling protocols, and aligning beyond-use claims with the function that CAR-T products must retain at administration.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key Words : CAR-T cell therapy, in-use stability, beyond-use date, functional potency, cryopreservation, advanced therapy medicinal products, infusion devices, regulatory harmonization
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