Chimeric antigen receptor T-cell therapy for acute myeloid leukemia: how close to reality?

Abstract

The approval of the anti-CD19 chimeric antigen receptor (CAR) T-cell product tisagenlecleucel (Kymriah®) by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for relapsed pediatric B-lineage acute lymphoblastic leukemia (B-ALL) was a landmark event in acute leukemia therapy. The approval was based on data from a phase II global trial in which 75 pediatric and young adult B-ALL patients received tisagenlecleucel, demonstrating safety, feasibility and biological response, with complete remissions (CR) at three months in 81% of patients, and event-free survival rates of 73% and 50% at six and 12 months, respectively.1 A detailed summary of the design and basic biology of CAR T cells was recently published, providing an excellent summary of the history and the current state of the field of CAR T-cell therapy for the treatment of malignant diseases.2 Unfortunately, the successes of CAR T cells in treating B-ALL have not yet been translated to the treatment of acute myeloid leukemia (AML), where progress has been delayed by the lack of a suitable targetable surface antigen. In BALL and other B-cell malignancies, elimination of malignant B cells occurs alongside that of normal B cells/B-cell progenitors. B-cell depletion has been clinically tolerated for years, since the ensuing hypogammaglobulinemia is easily corrected. In stark contrast, elimination of normal myeloid cells/progenitors is unlikely to be tolerated for long, as the targeted AML antigen is frequently co-expressed on healthy hematopoietic stem/progenitor cells (HSPC), leading to ablation of all myeloid progeny. Creative solutions are being sought to overcome these obstacles in order to make CART therapy a viable option for patients with AML. The current state of play: anti-acute myeloid leukemia chimeric antigen receptor T cells in the clinic Thirteen CART trials for patients with AML are currently enrolling patients (Table 1), though none have yet yielded mature published data. The first trial demonstrating biological activity for CART in AML was published in 2013, evaluating a second-generation (CD28 co-stimulatory domain) retrovirally transduced anti-Lewis Y CAR T-cell.3 Four of five enrolled patients with relapsed/refractory (RR) AML received a mean 4.46×106/kg CAR-positive T cells after lymphodepleting chemotherapy. The best responses achieved for each patient were: stable disease in two patients (for 49 days and 23 months respectively), reduction in blasts in one patient, and a cytogenetic remission in a patient with abnormal cytogenetics as the sole abnormality (i.e. blast count not elevated). Although all patients eventually progressed, this study was important as it demonstrated biological activity of CAR T cells against AML without significant hematopoietic toxicity, and the possibility of targeting a non-protein antigen.4 Table 1. Chimeric antigen receptor (CAR) T-cell therapy trials for patients with acute myeloid leukemia open for enrollment.