Distinct in vivo dynamics of donor-derived stem cell memory CAR T cells post-allogeneic HSCT relapse.
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- Record sourced from PubMed, PMID 42066750.
- Also identified by DOI 10.1016/j.cell.2026.03.047.
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Abstract
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 (T<sub>SCM</sub>) cells exhibited greater expansion and persistence than standard CAR T cells, enabling complete responses at low doses in the absence of lymphodepletion. CAR T<sub>SCM</sub> cells induced mild cytokine-release syndrome, dominated by IFN-γ. Both products differentiated into effectors; however, only CAR T<sub>SCM</sub> cells robustly reconstituted the stem-like compartment over time. CAR T<sub>SCM</sub> 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 T<sub>SCM</sub> cells was driven primarily by tumor- and host-related factors. These findings establish CAR T<sub>SCM</sub> cells as a promising platform for next-generation CAR T cell therapies.