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A Pathologist's Guide to Non-clinical Safety Assessment of Adoptive Cell Therapy Products
Alessandra Piersigilli1, Vinicius S Carreira2, Frédéric Gervais3
1Takeda Development Center Americas, Cambridge, MA, USA.
Abstract:
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.
Insights
Chimeric antigen receptor (CAR) T-cell therapies offer revolutionary cancer treatments but face challenges in preclinical safety assessment. Understanding CAR T-cell target expression and manufacturing is crucial for mitigating toxicities and improving patient outcomes.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Adoptive cell therapies (ACTs), specifically chimeric antigen receptor (CAR) T-cells, have transformed hematologic malignancy treatment.
- CAR T-cells function as engineered lymphocytes, targeting cancer cells independently of MHC, acting as adaptive
- living drugs
- post-treatment.
Purpose of the Study:
- To highlight the significant challenges in preclinical safety assessment for CAR T-cell therapies.
- To emphasize the need for a comprehensive understanding of factors influencing CAR T-cell safety and pharmacokinetics.
- To identify key areas for research to address CAR T-cell mediated toxicities.
Main Methods:
- Review of existing preclinical safety models for CAR T-cells.
- Analysis of factors influencing CAR T-cell safety and pharmacokinetics (donor/recipient characteristics, product design, manufacturing).
- Identification of primary CAR therapy-mediated toxicities in clinical settings.
Main Results:
- Existing preclinical models inadequately predict CAR T-cell safety and pharmacokinetics.
- CAR T-cell toxicities stem from off-target effects, potential tumorigenicity, and immune activation syndromes (CRS, ICANS).
- Numerous factors, including manufacturing processes, influence CAR T-cell behavior and safety.
Conclusions:
- Addressing CAR T-cell safety requires deeper insights into CAR target expression in normal tissues, including spatial distribution.
- Thorough off-target screening and understanding of manufacturing processes are essential.
- Further research into CAR cell immunopathology is critical for advancing safe and effective CAR T-cell therapies.
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