Distinct in vivo dynamics of donor-derived stem cell memory CAR T cells post-allogeneic HSCT relapse
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Donor-derived CD19-CAR T cells offer a therapeutic option for B cell malignancies relapsing after allogeneic hematopoietic stem cell transplantation but are often constrained by poor engraftment, expansion, and persistence. In a first-in-human study (NCT01087294), we found that CAR-modified stem-cell memory T (TSCM) cells exhibited greater expansion and persistence than standard CAR T cells, enabling complete responses at low doses in the absence of lymphodepletion. CAR TSCM cells induced mild cytokine-release syndrome, dominated by IFN-γ. Both products differentiated into effectors; however, only CAR TSCM cells robustly reconstituted the stem-like compartment over time. CAR TSCM cells were sustained through clonal succession, whereas persisting standard CAR T cells resulted from maintenance or contraction of early-expanded clones. While poor expansion limited standard CAR T cell activity, resistance to CAR TSCM cells was driven primarily by tumor- and host-related factors. These findings establish CAR TSCM cells as a promising platform for next-generation CAR T cell therapies.
Recommended citation: Gattinoni L, Inchingolo G, Harrer DC, Susana A, Puccio S, Slavkovic-Lukic D, Natrakul DA, Strieder N, Heuser-Loy C, Baldwin JG, Fioravanti J, Ji Y, Gautam S, Suriano C, Martín-Santos A, Schelker RC, Patel N, Mann J, Goff S, Mikkilineni L, Yang JC, Kwong MLM, Patel R, Rehli M, Highfill SL, Stroncek DF, Rosenberg SA, Biasco L, Lugli E, Brudno JN, Kochenderfer JN. Distinct in vivo dynamics of donor-derived stem cell memory CAR T cells post-allogeneic HSCT relapse. Cell 2026 Apr 30.
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