T-Charge™ Manufacturing of the Anti-BCMA CAR-T, Durcabtagene Autoleucel (PHE885), Promotes Expansion and Persistence of CAR-T Cells with High TCR Repertoire Diversity

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.3469-3469
• Main Authors: Ikegawa, Shuntaro, Sperling, Adam S., Ansuinelli, Michela, Nikiforow, Sarah, Quinn, David, Bu, Dexiu, Mataraza, Jennifer, Pearson, David, Rispoli, Lawrence, Credi, Marc A, Orwitz, Nina, Arihara, Yohei, Prabhala, Rao, Potluri, Lakshmi Bhavani, Reynolds, Carol, Vita, Serena De, Munshi, Nikhil C, Ritz, Jerome
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-177721

BCMA targeted CAR-T cells are an effective therapy for patients with relapsed or refractory multiple myeloma (r/r MM). However, autologous CAR-T cell products are highly heterogeneous and the functional roles of various T cell populations within these products have not been established. Stem-like memory T cells (Tscm) are a rare T cell subset which maintain high capacity for self-renewal and multipotency. Previously, we demonstrated that the T-Charge TM platform, a novel rapid manufacturing process that reduces manufacturing time to 5x10 6 cell dose (Sperling, ASCO 2023). CAR-T cells expanded rapidly after infusion reaching median peak levels of 3,118 cells/ul (range 373 to 17,865) with a median 87.4% (range, 46.9-97.8) of CD3+ T cells expressing the CAR at a median of 14 days (range 10 to 27) after infusion. CAR-T cells persisted at high levels with transgene detectable by qPCR in 67% of patients at 6 months. Among 28 evaluable patients, 13 (43%) had >20% CAR positive T cells detectable by flow cytometry at 3 months. Phenotypic analysis of APH and FP samples showed that less-differentiated T cell subsets, including Tscm and central memory T cells were maintained in FP. CyTOF evaluation of functional markers revealed high expression of proliferation and activation markers in Tscm in FP and subsequently in CAR-T cells at the time of peak expansion in vivo. Subsequently, more differentiated CAR-T cells increased, accompanied by a decline in activation markers, while no significant changes were observed in inhibitory receptors. The proportion of Tscm in the FP positively correlated with early in vivo CAR-T cell expansion. TCR repertoire diversity and TC