Advertisement

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 and Saar Gill

Key points

  • Depletion of CD123-redirected CAR T-cells with monoclonal antibodies preserves leukemia remission in human AML xenograft models.

  • AML CAR T-cell depletion enhances feasibility of subsequent allogeneic stem cell transplantation.

Abstract

Others and we previously reported potent anti-leukemia efficacy of CD123-redirected chimeric antigen receptor (CAR) T-cells in preclinical human acute myeloid leukemia (AML) models at cost of severe hematologic toxicity. This observation raises concern for potential myeloablation in patients with AML treated with CD123-redirected CAR T-cells and mandates novel approaches for toxicity mitigation. We hypothesized that 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 three CAR T-cell termination strategies: (1) transiently-active anti-CD123 mRNA-electroporated CART (RNA-CART123), (2) T-cell ablation with alemtuzumab after treatment with lentivirally-transduced anti-CD123-4-1BB-CD3ζ 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 studies demonstrated that durable leukemia remission required CAR T-cell persistence for 4 weeks prior to ablation. Upon CAR T-cell termination, we further demonstrated successful hematopoietic engraftment with a normal human donor to 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.

  • Submitted August 26, 2016.
  • Accepted February 21, 2017.