Luca Gattinoni, Gabriele Inchingolo, Dennis Christoph Harrer, Alberto Susana, Simone Puccio, Dragana Slavkovic‐Lukic, Danielle Natrakul, Nicholas Strieder, Christoph Heuser-Loy, Jeremy Baldwin, Jessica Fioravanti, Yun Ji, Sanjivan Gautam, Chiara Suriano, Azucena Martín-Santos, Roland Christian Schelker, Nisha Patel, Jennifer Mann, Stephanie L. Goff, Lekha Mikkilineni, James C. Yang, Mei Li M. Kwong, Rashmika Patel, Michael Rehli, Steven L. Highfill, David F. Stroncek, S A. Rosenberg, Luca Biasco, Enrico Lugli, Jennifer N. Brudno, James N. Kochenderfer
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 SCM ) cells exhibited greater expansion and persistence than standard CAR T cells, enabling complete responses at low doses in the absence of lymphodepletion. CAR T SCM cells induced mild cytokine-release syndrome, dominated by IFN-γ. Both products differentiated into effectors; however, only CAR T SCM cells robustly reconstituted the stem-like compartment over time. CAR T SCM 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 SCM cells was driven primarily by tumor- and host-related factors. These findings establish CAR T SCM cells as a promising platform for next-generation CAR T cell therapies.