Elsevier

The Lancet

Volume 385, Issue 9967, 7–13 February 2015, Pages 517-528
The Lancet

Articles
T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial

https://doi.org/10.1016/S0140-6736(14)61403-3Get rights and content

Summary

Background

Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells.

Methods

This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1–30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 106 CAR-transduced T cells per kg (dose 1), 3 × 106 CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696.

Findings

Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 106 CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0–36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients).

Interpretation

CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur.

Funding

National Institutes of Health Intramural funds and St Baldrick's Foundation.

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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