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Acute myelogenous leukemia

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia

Leukemia volume 29, pages 1637–1647 (2015)Cite this article

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Abstract

Patients with chemo-refractory acute myeloid leukemia (AML) have a dismal prognosis. Chimeric antigen receptor T (CART) cell therapy has produced exciting results in CD19+ malignancies and may overcome many of the limitations of conventional leukemia therapies. We developed CART cells to target CD33 (CART33) using the anti-CD33 single chain variable fragment used in gemtuzumab ozogamicin (clone My96) and tested the activity and toxicity of these cells. CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts. CART33 also resulted in human lineage cytopenias and reduction of myeloid progenitors in xenograft models of hematopoietic toxicity, suggesting that permanently expressed CD33-specific CART cells would have unacceptable toxicity. To enhance the viability of CART33 as an option for AML, we designed a transiently expressed mRNA anti-CD33 CAR. Gene transfer was carried out by electroporation into T cells and resulted in high-level expression with potent but self-limited activity against AML. Thus our preclinical studies show potent activity of CART33 and indicate that transient expression of anti-CD33 CAR by RNA modification could be used in patients to avoid long-term myelosuppression. CART33 therapy could be used alone or as part of a preparative regimen prior to allogeneic transplantation in refractory AML.

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Acknowledgements

This work was funded by a research agreement with Novartis Pharmaceuticals, a Leukemia and Lymphoma Society Specialized Centers of Research grant to CHJ, a National Institutes of Health T32 award to MK (T32-GM008076) and an American Society of Hematology Scholar award to SG. We thank Fang Chen and Simon Lacey for performing Luminex assay. Imaging was performed at the University of Pennsylvania Small Animal Imaging Facility (SAIF) Optical/Bioluminescence Core, supported by NIH grant CA016520.

Author Contributions

SSK designed and performed research, analyzed data and wrote the paper; MR and SG designed, performed research and wrote the paper; OS performed research, MK, VA, JM and DS performed research; JS contributed reagents and performed research; DLP designed research and wrote the paper; MC designed research and contributed reagents; and CHJ designed research, contributed reagents and wrote the paper. All authors read and approved the manuscript.

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  1. S S Kenderian and M Ruella: These authors contributed equally to this work.

Authors and Affiliations

  1. Translational Research Program, Abramson Family Research Cancer Institute, University of Pennsylvania, Philadelphia, PA, USA

    S S Kenderian, M Ruella, O Shestova, M Klichinsky, J Scholler, D Song, D L Porter, C H June & S Gill

  2. Division of Hematology and Bone Marrow Transplantation, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

    S S Kenderian

  3. Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA

    V Aikawa & J J D Morrissette

  4. Department of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA

    D L Porter, M Carroll & S Gill

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Correspondence to S Gill.

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Competing interests

CHJ and DLP have filed patent applications related to CAR technology and could potentially receive licensing royalties from Novartis corporation. The other authors declare no conflict of interest.

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Kenderian, S., Ruella, M., Shestova, O. et al. CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia 29, 1637–1647 (2015). https://doi.org/10.1038/leu.2015.52

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