Journal
BLOOD
Volume 129, Issue 17, Pages 2395-2407Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-08-736041
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Funding
- National Institutes of Health
- National Cancer Institute [K08CA184418, K08CA194256, K12CA090628]
- Cookies for Kids' Cancer Foundation
- Press On Foundation
- Andrew McDonough B+ Foundation
- Gabrielle's Angel Foundation for Cancer Research
- Stand Up to Cancer-St. Baldrick's Foundation Pediatric Dream Team Translational Research Grant [SU2C-AACR-DT1113]
- Predolin Foundation
- Novartis Pharmaceuticals
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We and others previously reported potent antileukemia efficacy of CD123-redirected chimeric antigen receptor (CAR) T cells in preclinical human acute myeloid leukemia (AML) models at the 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 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-CD3 zeta 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 CART-cell persistence for 4 weeks prior to ablation. Upon CART-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 CART-cell therapy for patients with AML.
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