Choice of activation protocol impacts the yield and quality of CAR T cell product, particularly with older individuals

Choice of activation protocol impacts the yield and quality of CAR T cell product, particularly with older individuals

Abstract Objectives In clinical chimeric antigen receptor (CAR) T cell therapy, one of the strongest correlates of favorable patient responses is lower levels of differentiation in T cells from the peripheral blood mononuclear cell (PBMC) starting material or the CAR T cell product. T cells from old...

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Main Authors: Palak H Mehta, Gemma S Trollope, Patrick Leung, Shivali Savita Chinni, Anna Iasinskaia, Aaron J Harrison, Hannah Hughes‐Parry, Misty R Jenkins, Michael H Kershaw, Anthony Jaworowski, Clare Y Slaney, Rachel M Koldej, David S Ritchie, Kylie M Quinn
Format: Article
Language:English
Published: Wiley 2024-01-01
Series:Clinical & Translational Immunology
Subjects:
ageing
CAR T cell
CD28
T cell activation
Online Access:https://doi.org/10.1002/cti2.70016
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Summary:Abstract Objectives In clinical chimeric antigen receptor (CAR) T cell therapy, one of the strongest correlates of favorable patient responses is lower levels of differentiation in T cells from the peripheral blood mononuclear cell (PBMC) starting material or the CAR T cell product. T cells from older patients are inherently more differentiated, but we hypothesised that specific activation protocols could be used to limit CAR T cell differentiation during manufacturing, particularly in older patients. Methods We used PBMCs from young (20–30 years old) and older (60+ years old) healthy donors to generate CAR T cells using two activation protocols: soluble anti‐(α) CD3 monoclonal antibody (mAb) vs immune complexes of αCD3 and αCD28 mAbs. Products were assessed for yield, function and differentiation, which was used as a measure of CAR T cell quality. T cells in PBMCs were assessed for CD28 expression and correlative analyses were performed. Results Older samples generated fewer, more differentiated CAR T cells than young samples, and the αCD3/CD28 mAb protocol exacerbated this, further reducing yield and quality. CD28 expression by T cells correlated with CAR T cell differentiation, but T cell differentiation in PBMC starting material was a stronger correlate of CAR T cell differentiation. Conclusions Choice of activation protocol can substantially impact on the yield and quality of CAR T cells during manufacturing. This is a key consideration for older patients whose samples already generate a poorer yield and lower quality of CAR T cells.
ISSN:2050-0068

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