Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults

Rebecca A. Gardner, Olivia Finney, Colleen Annesley, Hannah Brakke, Corinne Summers, Kasey Leger, Marie Bleakley, Christopher Brown, Stephanie Mgebroff, Karen Spratt, Virginia Hoglund, Catherine Lindgren, Assaf P. Oron, Daniel Li, Stanley R. Riddell, Julie R. Park and Michael C. Jensen

Key points

  • Defined composition manufacturing platform of CD19CAR T cells contributes to >90% intent to treat CR rate.

  • Uniformity of durable persistence of CAR T cells and mitigation of antigen escape are key aspects for further optimization.


Transitioning CD19-directed CAR-T cells from early phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application in patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage ALL was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled subjects. The maximal tolerated dose (MTD) was 106 CAR-T cells/kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat (ITT) minimal residual disease (MRD)-negative remission rate for this Phase I study was 89%. An MRD-negative remission rate measured among subjects who received a CAR T cell product was 93%, and 100% in the subset of patients that received flu/cy lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome (sCRS) and/or reversible severe neurotoxicity (sNT). These data demonstrate that manufacturing a defined composition CD19 CAR-T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable side effect profile in a cohort of patients with an otherwise dismal prognosis.

  • Submitted February 17, 2017.
  • Accepted April 4, 2017.