Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults

Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults
Autologous T-cells expressing CD19-specific chimeric antigen receptor (CAR) can induce remission in B-lineage leukemias, specifically refractory ALL, regardless of disease burden. Treatment has been limited by high failure rate in CAR T-cell manufacturing, heterogeneity of response, and treatment associated toxicities.
The authors developed a streamlined manufacturing process for CAR T-cells from a single apheresis product, with a defined 1:1 ratio of CD4/CD8 CAR T cells and selected for high CAR production. Cytokine cocktails were designed to produce homogeneous T-cell differentiation for engraftment fitness. Feasibility of the process, clinical efficacy, and toxicity was evaluated in 45 patients with relapsed or refractory CD19+ ALL. Patients had a varied disease burden and a variable prior treatment history, including some patients who had previously received hematopoeitic stem cell transplantation or CD19 directed therapy.
The manufacturing process was highly successful (100% in minimally pretreated and 93% in heavily pretreated patients), and detectable engraftment was observed in 98% of patients at a median of 10 days. Pretreatment lymphodepletion with both fludarabine and cyclophosphamide was more effective that cyclophosphamide alone. At a median follow up time of 9.6 months, EFS is 50.8% with OS of 69.5%. B-cell aplasia was used as a marker of functional CAR T-cell activity, and observed in 93% of patients - loss of B-cell aplasia was correlated with risk of leukemic relapse, with a hazard ratio of 34. Cytokine release syndrome and neurotoxicity were the most common adverse events, but there were no deaths from toxicity.
While the authors comment in the results about the variable success depending on the lymphodepletion regimen, the actual protocol is not specified in the Methods, nor do they explain how they determined which patients would be given fludarabine. As well, the variety of patients included support the potential role of this therapy in difficult to treat disease, but make it difficult to extrapolate recommendations for any one disease state.
Manufacturing of CAR T-cells using cell purification, enriched transgene expression, and cocktails of recombinant cytokines can reproducibly produce products with therapeutic potency. The use of lymphodepletion with both fludarabine and cyclophosphamide may be associated with better persistence and effect of the CAR T-cells.