Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia

Sarah K. Tasian, Saad S. Kenderian, Feng Shen, Marco Ruella, Olga Shestova, Miroslaw Kozlowski, Yong Li, April Schrank-Hacker, Jennifer J.D. Morrissette, Martin Carroll, Carl H. June, Stephan A. Grupp, Saar Gill

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

We and others previously reported potent antileukemia efficacy of CD123-redirected chimeric antigen receptor (CAR) T cells in preclinical human acute myeloid leukemia (AML) modelsat the costof severe hematologic toxicity. This observation raises concern for potential myeloablation in patients with AML treated with CD123-redirected CAR Tcells andmandatesnovel approaches for toxicitymitigation.Wehypothesizedthat CAR T-cell depletion with optimal timing after AML eradication would preserve leukemia remission and allow subsequent hematopoietic stem cell transplantation. To test this hypothesis, we compared 3 CAR T-cell termination strategies: (1) transiently active anti-CD123 messenger RNA-electroporated CART (RNA-CART123); (2) T-cell ablation with alemtuzumab after treatment with lentivirally transduced anti-CD123-4-1BB-CD3z T cells (CART123); and (3) T-cell ablation with rituximab after treatment with CD20-coexpressing CART123 (CART123-CD20). All approaches led to rapid leukemia elimination in murine xenograft models of human AML. Subsequent antibody-mediated depletion of CART123 or CART123-CD20 did not impair leukemia remission. Time-course studiesdemonstrated that durableleukemiaremission required CART-cellpersistencefor4weekspriortoablation.Upon CAR T-celltermination,wefurther demonstrated successful hematopoietic engraftment witha normal human donorto model allogeneic stem cell rescue. Results from these studies will facilitate development of T-cell depletion strategies to augment the feasibility of CAR T-cell therapy for patients with AML.

Original languageEnglish (US)
Pages (from-to)2395-2407
Number of pages13
JournalBlood
Volume129
Issue number17
DOIs
StatePublished - Apr 27 2017

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Tasian, S. K., Kenderian, S. S., Shen, F., Ruella, M., Shestova, O., Kozlowski, M., Li, Y., Schrank-Hacker, A., Morrissette, J. J. D., Carroll, M., June, C. H., Grupp, S. A., & Gill, S. (2017). Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. Blood, 129(17), 2395-2407. https://doi.org/10.1182/blood-2016-08-736041