Distinct in vivo dynamics of donor-derived stem cell memory CAR T cells post-allogeneic HSCT relapse.
Luca Gattinoni, Gabriele Inchingolo, Dennis C Harrer, Alberto Susana, Simone Puccio, Dragana Slavkovic-Lukic, Danielle A Natrakul, Nicholas Strieder, Christoph Heuser-Loy, Jeremy G Baldwin, Jessica Fioravanti, Yun Ji, Sanjivan Gautam, Chiara Suriano, Azucena Martín-Santos, Roland C Schelker, Nisha Patel, Jennifer Mann, Stephanie Goff, Lekha Mikkilineni, James C Yang, Mei Li M Kwong, Rashmika Patel, Michael Rehli, Steven L Highfill, David F Stroncek, Steven A Rosenberg, Luca Biasco, Enrico Lugli, Jennifer N Brudno, James N Kochenderfer
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 (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.