Abstract
As significant numbers of acute myeloid leukemia (AML) patients are still refractory to conventional therapies or experience relapse, immunotherapy using T cells expressing chimeric antigen receptors (CARs) might represent a valid treatment option. AML cells frequently overexpress the myeloid antigens CD33 and CD123, for which specific CARs can be generated. However, CD33 is also expressed on normal hematopoietic stem/progenitor cells (HSPCs), and its targeting could potentially impair normal hematopoiesis. In contrast, CD123 is widely expressed by AML, while low expression is detected on HSPCs, making it a much more attractive target. In this study we describe the in vivo efficacy and safety of using cytokine-induced killer (CIK) cells genetically modified to express anti-CD33 or anti-CD123 CAR to target AML. We show that both these modified T cells are very efficient in reducing leukemia burden in vivo, but only the anti-CD123 CAR has limited killing on normal HSPCs, thus making it a very attractive immunotherapeutic tool for AML treatment.
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Acknowledgements
We thank Dr Alfredo Pagliuca for providing us with the Luciferase constructs. We would like to thanks Drs Gino Vairo and Angel Lopez from CSL Limited Australia, for providing us with the initial CD123 mAb from which we derived the CAR. This work was funded in part by Cancer Research UK to DB and by Fondazione Tettamanti and Associazione Italiana per la Ricerca sul Cancro (AIRC) (AIRC 5 × 1000; AIRC-IG8666) to AB.
Author contributions
IP designed and coordinated the research, performed experiments, analyzed the data and wrote the paper. FAA performed the experiments, interpreted the results, revised the data and wrote the paper. KRP and FL performed the experiments. ST and OS provided AML samples and performed the experiments. AB, EB and BD designed and coordinated the research, revised the data and wrote the paper.
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Pizzitola, I., Anjos-Afonso, F., Rouault-Pierre, K. et al. Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo. Leukemia 28, 1596–1605 (2014). https://doi.org/10.1038/leu.2014.62
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DOI: https://doi.org/10.1038/leu.2014.62
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