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Ferrata Storti Foundation
Haematologica 2019 Volume 104(7):1302-1308
Chimeric antigen receptor T-cell therapy for acute myeloid leukemia: how close to reality?
Katherine D. Cummins and Saar Gill
Division of Hematology-Oncology and Center for Cellular Immunotherapies, University of Pennsylvania, PA, USA
Introduction
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 lym- phoblastic 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, feasi- bility 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 B- ALL and other B-cell malignancies, elimination of malignant B cells occurs along- side 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, eval- uating 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 4.46x106/kg CAR-positive T cells after lymphodeplet- ing chemotherapy. The best responses achieved for each patient were: stable dis- ease 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 cytogenet- ics 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
Two attractive targets for CART therapy in AML are CD33 and CD123. Both antigens are almost ubiquitous on AML blasts, though both are also present on normal HSPC.5,6 Published data for CART33 are limited; a case report from 2015 describes a 41-year old patient who had a transient response to CART33,7 and two patients who demonstrated a clinical response to a combined CD33-CLL1 CART (CLL1=C-type lectin molecule-1) were reported at the American Society of Hematology (ASH) annual meeting in 2018,8 though no data have been presented to date for the rest of this cohort (clinicaltrials.gov identifier: 03795779).
CD123 is a particularly attractive antigen due to both its expression on other hematologic malignancies,9 and its credentials as a potential marker of leukemia- initiating cells (LIC).10 Given the shared expression of CD123 on both healthy and malignant blasts, it is anticipated that patients responding to CART123 are likely to require a rescue allogeneic stem cell transplant (alloHSCT), a hypothesis sup- ported by our pre-clinical data indicating myeloablation and AML eradication by
Correspondence:
SAAR GILL
saargill@pennmedicine.upenn
Received: February 10, 2019. Accepted: March 26, 2019. Pre-published: June 20, 2019.
doi:10.3324/haematol.2018.208751
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/7/1302
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