Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Hematology Disease Topics & Pathways:
Biological therapies, Research, adult, Translational Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Plasma Cell Disorders, Diseases, immune mechanism, Therapies, immunology, Lymphoid Malignancies, Biological Processes, Human, Study Population
We previously reported a 98% overall response rate (ORR) across all dose levels (2.5-20x106 CAR-T cells) and 100% ORR at doses >5x106 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 TCR clone tracking were used to characterize product manufacturing and CAR-T cells in peripheral blood after infusion. We sorted naïve/Tscm CD4 T cells, naïve/Tscm CD8 T cells, memory CD4 T cells, and memory CD8 T cells from APH and FP, and isolated CAR-positive CD4 T cells, CAR-positive CD8 T cells, CAR-negative CD4 cells, and CAR-negative CD8 T cells from post-infusion PBMC by fluorescence-activated cell sorting and ran TCR sequence from the extracted gDNA from each T cell subpopulation. Measurement of TCR diversity post-infusion revealed higher TCR repertoire diversity in CAR-T cells than in non-CAR-T cells. Notably, post-infusion CAR-T cells shared significantly more TCR clonotypes with TSCM than with memory T cells in the FP, suggesting that the highly heterogeneous post-infusion CAR-T clones were preferentially derived from TSCM clones in the FP. In three evaluable patients with long-term persistence, a highly diverse TCR repertoire in CAR T cells was maintained 1 year after treatment.
Our findings demonstrate that the T-Charge™ manufacturing platform successfully maintains highly heterogeneous transduced Tscm clones with self-renewal potential in durcabtagene autoleucel products. Maintenance of Tscm in manufactured products contributes to robust CAR-T expansion and long-term persistence of CAR-T cells with a highly diverse TCR repertoire after infusion.
Disclosures: Ikegawa: Kyowa Kirin: Honoraria. Sperling: Roche: Consultancy; Novartis: Consultancy. Nikiforow: Sobi: Other: Participation in ad hoc advisory board; Kite/Gilead: Other: Participation in ad hoc advisory board; Iovance: Other: Participation in ad hoc advisory board; GlaxoSmithKline: Other: Participation in ad hoc advisory board; A2 Bio: Other: Participation in ad hoc advisory board. Quinn: Novartis: Current Employment. Bu: Novartis: Current Employment. Mataraza: Novartis: Current Employment. Pearson: Novartis: Current Employment. Rispoli: Novartis: Current Employment. Credi: Novartis: Current Employment. Orwitz: Novartis: Current Employment. Vita: Novartis: Current Employment. Ritz: Oncternal: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite/Gilead: Research Funding; Garuda Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; LifeVault Bio: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Clade Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Smart Immune: Consultancy, Membership on an entity's Board of Directors or advisory committees; TScan Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Equillium: Research Funding; Avrobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Akron Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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