Abstract
CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumour activity in B cell malignancies, but factors that impact outcomes have been difficult to define in part due to variability in the composition of the infused CAR-T cell products. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a uniform 1:1 CD4+:CD8+ ratio of CAR-T cells to adults with relapsed and/or refractory B cell non-Hodgkin lymphoma or chronic lymphocytic leukaemia after lymphodepletion chemotherapy.1,2 We defined factors affecting CAR-T cell expansion in vivo and the anti-tumour efficacy and toxicity of treatment. Patients who received cyclophosphamide (Cy)-based lymphodepletion chemotherapy with fludarabine (Flu) had markedly increased CAR-T cell expansion and persistence, and higher response rates than patients who received Cy-based lymphodepletion without Flu. Cy/Flu minimised the effects of an immune response to the murine scFv component of the CAR, which limited efficacy in patients who received Cy-based lymphodepletion without Flu. The beneficial effect of the addition of Flu was also associated with elevated serum concentrations of homeostatic cytokines before CAR-T cell infusion.
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