Chimeric antigen receptor T-cell therapies in acute myeloid leukaemia

Author: Dr Koon Lee (MA MBBchir FRACP FRCPA.)

Chimeric antigen receptor (CAR) T-cell therapies in the form of CD19-specific CARs have produced remarkable outcomes in relapsed and refractory B-cell malignancies. However, replicating this success in acute myeloid leukaemia (AML) is not straightforward. The heterogeneity of overexpressed antigens in AML prevents a one-size-fits-all approach and predisposes to treatment resistance and failure. In addition, there is significant overlap of potential target antigens with normal myeloid and haematopoietic progenitors, which could lead to intolerable myelosuppression due to ‘on-target, off tumour’ toxicity.

Some of the AML targets being explored for CAR T-cell therapies include the myeloid antigens CD33, CD123, C-type lectin-like molecule-1 (CLL-1) and the inducible natural killer group 2D (NKG2D) ligands1‑4. Of the trials reported, complete remissions have been achieved in a small number of patients2,4. Dual- and multiple-antigen targeting approaches to prevent resistance and treatment failure are also in trials.5

The use of CAR T-cell therapies in AML in clinical trials have often been in concert with consolidative allogeneic haematopoietic stem cell transplant to try over-come treatment resistance and prolonged myelosuppression. An innovative approach has also been described whereby healthy allogeneic haematopoietic stem cells are genetically edited to remove CD33 expression, rendering them resistant to anti-CD33 CAR T-cell therapy6.

Alternatively, by designing CARs which target a combination of antigens, it may be possible to preferentially and specifically target AML blasts, sparing normal healthy tissue. The synthetic Notch (synNotch) system allows for conditional expression of CAR against a second antigen when the presence of a first target antigen is detected7, while the more recently described co-localisation dependent protein switches (Co-LOCKR) approach, goes a further step, and is only activated in the presence of both target antigens8.

While the implementation of CAR T-cell therapies in AML has been hampered by the biological reasons outlined, preliminary results from clinical trials are promising. With newer tools now available to address toxicity and resistance, it is hoped that CAR T-cell therapies will improve the outcome of relapsed and refractory AML in the future.

Bio: Dr Koon Lee is a staff specialist clinical and laboratory Haematologist at Gosford and Wyong Hospitals. He is a PhD candidate at the University of Sydney performing research in T-cell therapies in acute myeloid leukaemia at Westmead Institute for Medical Research with the Cellular Therapies Research Group.

References:

1. Wang QS, et al. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther 2015;23(1):184-91.

2. Budde L, et al. Remissions of acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm following treatment with CD123-specific CAR T cells: A first-in-human clinical trial. Blood 2017;130(Suppl 1):811.

3. Wang J, et al. CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia. J Hematol Oncol 2018;11:7.

4. Baumeister SH, et al. Phase I trial of autologous CAR T cells targeting NKG2D ligands in patients with AML/MDS and multiple myeloma. Cancer Immunol Res 2019;7(1):100-12.

5. Petrov JC, et al. Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia. Leukemia 2018;32(6):1317-26.