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

Sarah K. Tasian, Saad 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

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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

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T-cells
T-Cell Antigen Receptor
Heterografts
Acute Myeloid Leukemia
Antigen Receptors
T-Lymphocytes
Ablation
Stem cells
Leukemia
Hematopoietic Stem Cell Transplantation
Toxicity
Cell- and Tissue-Based Therapy
RNA
Stem Cells
Messenger RNA
Antibodies
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. / Tasian, Sarah K.; Kenderian, Saad; Shen, Feng; Ruella, Marco; Shestova, Olga; Kozlowski, Miroslaw; Li, Yong; Schrank-Hacker, April; Morrissette, Jennifer J.D.; Carroll, Martin; June, Carl H.; Grupp, Stephan A.; Gill, Saar.

In: Blood, Vol. 129, No. 17, 27.04.2017, p. 2395-2407.

Research output: Contribution to journalArticle

Tasian, SK, Kenderian, S, Shen, F, Ruella, M, Shestova, O, Kozlowski, M, Li, Y, Schrank-Hacker, A, Morrissette, JJD, Carroll, M, June, CH, Grupp, SA & Gill, S 2017, 'Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia', Blood, vol. 129, no. 17, pp. 2395-2407. https://doi.org/10.1182/blood-2016-08-736041
Tasian, Sarah K. ; Kenderian, Saad ; Shen, Feng ; Ruella, Marco ; Shestova, Olga ; Kozlowski, Miroslaw ; Li, Yong ; Schrank-Hacker, April ; Morrissette, Jennifer J.D. ; Carroll, Martin ; June, Carl H. ; Grupp, Stephan A. ; Gill, Saar. / Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. In: Blood. 2017 ; Vol. 129, No. 17. pp. 2395-2407.
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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.",
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AU - Kenderian, Saad

AU - Shen, Feng

AU - Ruella, Marco

AU - Shestova, Olga

AU - Kozlowski, Miroslaw

AU - Li, Yong

AU - Schrank-Hacker, April

AU - Morrissette, Jennifer J.D.

AU - Carroll, Martin

AU - June, Carl H.

AU - Grupp, Stephan A.

AU - Gill, Saar

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N2 - 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.

AB - 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.

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