Combinatorial antigen targeting strategies for acute leukemia: application in myeloid malignancy |
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| Institution: | 1. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA;2. Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA;3. Texas Children''s Cancer Center, Texas Children''s Hospital, Houston, Texas, USA;4. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA;5. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA;1. Center for Regenerative Medicine and Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, Florida, USA;2. Cell Therapy Research Laboratories, Daiichi Sankyo, Co., Ltd., Tokyo, Japan;1. Canadian Blood Services, Ottawa, Ontario, Canada;2. Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada;3. The Ottawa Hospital, Ottawa, Ontario, Canada;4. Centre for Innovation, Canadian Blood Services, Edmonton, Alberta, Canada;1. GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India;2. Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India;3. Stem Cell Research Laboratory, GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India;1. Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy;2. Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy;1. Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg, Germany;2. Department of Hematology, the Affiliated Hospital of Guizhou Medical University, Guizhou, China;3. Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China;4. Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, China;5. Department of Internal Medicine C, Haematology, Oncology, Stem Cell Transplantation, Palliative Care, University Clinic Greifswald, Greifswald, Germany |
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| Abstract: | Background aimsEfforts to safely and effectively treat acute myeloid leukemia (AML) by targeting a single leukemia-associated antigen with chimeric antigen receptor (CAR) T cells have met with limited success, due in part to heterogeneous expression of myeloid antigens. The authors hypothesized that T cells expressing CARs directed toward two different AML-associated antigens would eradicate tumors and prevent relapse.MethodsFor co-transduction with the authors’ previously optimized CLL-1 CAR currently in clinical study (NCT04219163), the authors generated two CARs targeting either CD123 or CD33. The authors then tested the anti-tumor activity of T cells expressing each of the three CARs either alone or after co-transduction. The authors analyzed CAR T-cell phenotype, expansion and transduction efficacy and assessed function by in vitro and in vivo activity against AML cell lines expressing high (MOLM-13: CD123 high, CD33 high, CLL-1 intermediate), intermediate (HL-60: CD123 low, CD33 intermediate, CLL-1 intermediate/high) or low (KG-1a: CD123 low, CD33 low, CLL-1 low) levels of the target antigens.ResultsThe in vitro benefit of dual expression was most evident when the target cell line expressed low antigen levels (KG-1a). Mechanistically, dual expression was associated with higher pCD3z levels in T cells compared with single CAR T cells on exposure to KG-1a (P < 0.0001). In vivo, combinatorial targeting with CD123 or CD33 and CLL-1 CAR T cells improved tumor control and animal survival for all lines (KG-1a, MOLM-13 and HL-60); no antigen escape was detected in residual tumors.ConclusionsOverall, these findings demonstrate that combinatorial targeting of CD33 or CD123 and CLL-1 with CAR T cells can control growth of heterogeneous AML tumors. |
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