A Pathologist's Guide to Non-clinical Safety Assessment of Adoptive Cell Therapy Products.
| Autor: | Piersigilli A; Takeda Development Center Americas, Cambridge, MA, USA., Carreira VS; Johnson & Johnson Innovative Medicine, San Diego, CA, USA., Gervais F; Charles River Laboratories, Evreux, France., Mansfield K; Novartis, Cambridge, MA, USA., McIntosh BE; Labcorp, Madison, WI, USA., Cornax I; Altos Labs, Redwood City, CA, USA. |
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| Jazyk: | angličtina |
| Zdroj: | Toxicologic pathology [Toxicol Pathol] 2024 Dec 06, pp. 1926233241298570. Date of Electronic Publication: 2024 Dec 06. |
| DOI: | 10.1177/01926233241298570 |
| Abstrakt: | Through two decades of research and development, adoptive cell therapies (ACTs) have revolutionized treatment for hematologic malignancies. Many of the seven US Food and Drug Administration (FDA)-approved products are proven to be a curative last line of defense against said malignancies. The ACTs, known more commonly as chimeric antigen receptor (CAR) T-cells, utilize engineered lymphocytes to target and destroy cancer cells in a patient-specific, major histocompatibility complex (MHC)-independent manner, acting as "living drugs" that adapt to and surveil the body post-treatment. Despite their efficacy, CAR T-cell therapies present unique challenges in preclinical safety assessment. The safety and pharmacokinetics of CAR T-cells are influenced by numerous factors including donor and recipient characteristics, product design, and manufacturing processes that are not well-predicted by existing in vitro and in vivo preclinical safety models. The CAR therapy-mediated toxicities in clinical settings primarily arise from unintended targeting of non-tumor cells, potential tumorigenicity, and severe immune activation syndromes like cytokine release syndrome and immune effector cell-associated neurotoxicity. Addressing these issues necessitates a deep understanding of CAR target expression in normal tissues, inclusive of the spatial microanatomical distribution, off-target screening, and a deep understanding CAR cell manufacturing practices and immunopathology. Competing Interests: Declaration of Conflicting InterestsFG works at Charles Rivers Laboratories the vendor of Retrogenix technology. The author(s) declared no other potential conflicts of interest with respect to the research, authorship, and/or publication of this article. |
| Databáze: | MEDLINE |
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