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 language | English (US) |
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Pages (from-to) | 2395-2407 |
Number of pages | 13 |
Journal | Blood |
Volume | 129 |
Issue number | 17 |
DOIs | |
State | Published - Apr 27 2017 |
ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology