Distinct in vivo dynamics of donor-derived stem cell memory CAR T cells post-allogeneic HSCT relapse.

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.