ArticlesT cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial
Introduction
B-precursor acute lymphoblastic leukaemia (B-ALL) is the most common malignancy in childhood. Newly diagnosed children have about 90% survival, but cure needs prolonged therapy with substantial short-term and long-term toxicities.1, 2 Adults with B-ALL have lower survival rates, partly because of a high frequency of subtypes with less chemosensitivity.3, 4 Irrespective of age, patients with primary or recurrent refractory B-ALL who do not have complete remission negative for minimum residual disease (MRD) with cytotoxic chemotherapy have dismal survival rates of less than 10%, and outcomes for these patients have not improved substantially in the last two decades.5, 6, 7
Chimeric antigen receptors (CARs) incorporate an antigen recognition sequence, such as a single-chain variable fragment (scFv) of a monoclonal antibody, with intracellular signalling domains that activate the T cell.8 Although several case series have reported antitumour effects of autologous CD19-directed CAR T cells in patients with B-cell lymphoma,9, 10 chronic lymphocytic leukaemia,11, 12 and B-ALL,12, 13, 14, 15 results of an intention-to-treat protocol of sequentially enrolled patients treated with a consistent regimen has not been reported. In this phase 1 trial we define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in 21 consecutively enrolled children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells.
Section snippets
Study design and participants
We did an open-label, phase 1 dose-escalation study of CD19-CAR T cells in children and young adults with ALL or non-Hodgkin lymphoma. Patients were screened and treated in the Pediatric Oncology Branch of the National Cancer Institute (NCI) at the Clinical Center of the US National Institutes of Health. Data are presented until July 18, 2014, and responding patients continue to be followed up for survival, relapse, and as mandated by the US Food and Drug Administration (FDA),16 which requires
Results
Between July 2, 2012, and June 20, 2014, 21 patients were enrolled and all received CAR T cells. Table 1 shows patient demographics and clinical characteristics. All were heavily pretreated with cytotoxic chemotherapy (appendix). Six patients with B-ALL had primary refractory disease and had never attained an MRD-negative remission despite many intensive chemotherapy regimens. Eight had previously undergone allogeneic HSCT. One patient had previously received CD19-CAR T-cell therapy at another
Discussion
CARs provide a potent new approach for cancer immunotherapy. This first intention-to-treat analysis of consecutively enrolled patients on a clinical trial of CD19-CAR T cells for refractory B-cell malignancies shows that CD19-CAR therapy is feasible for a high proportion of patients with refractory B-ALL, induced a complete response in 70% of patients with B-ALL and an MRD-negative complete response in 60%, and a 78·8% probability of those rendered into an MRD-negative complete response remain
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