Journal
PLOS ONE
Volume 11, Issue 8, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0159477
Keywords
-
Categories
Funding
- Cancer Center Core Grant [CA16672]
- SPORES [CA100632, CA136411, CA00632]
- Albert J Ward Foundation
- Alex's Lemonade Stand Foundation
- Burroughs Wellcome Fund
- Cancer Prevention and Research Institute of Texas
- Charles B. Goddard Foundation of Texas
- CLL Global Research Foundation
- Energy Transfer Partners
- Estate of Noelan L. Bibler
- Gillson Longenbaugh Foundation
- Harry T. Mangurian, Jr., Fund for Leukemia Immunotherapy
- Khalifa Bin Zayed Al Nahyan Foundation
- Kleberg Foundation
- Leukemia and Lymphoma Society
- Lymphoma Research Foundation
- Miller Foundation
- National Foundation for Cancer Research
- Pediatric Cancer Research Foundation
- Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
- University of Texas MD Anderson Cancer Center Sister Institution Network Fund
- University of Texas MD Anderson Cancer Center Moon Shot Fund
- William Lawrence and Blanche Hughes Children's Foundation
- [CA124782]
- [CA120956]
- [CA141303]
- [CA148600]
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Adoptive immunotherapy infusing T cells with engineered specificity for CD19 expressed on B-cell malignancies is generating enthusiasm to extend this approach to other hematological malignancies, such as acute myelogenous leukemia (AML). CD123, or interleukin 3 receptor alpha, is overexpressed on most AML and some lymphoid malignancies, such as acute lymphocytic leukemia (ALL), and has been an effective target for T cells expressing chimeric antigen receptors (CARs). The prototypical CAR encodes a V-H and V-L from one monoclonal antibody (mAb), coupled to a transmembrane domain and one or more cytoplasmic signaling domains. Previous studies showed that treatment of an experimental AML model with CD123-specific CAR T cells was therapeutic, but at the cost of impaired myelopoiesis, highlighting the need for systems to define the antigen threshold for CAR recognition. Here, we show that CARs can be engineered using V-H and V-L chains derived from different CD123-specific mAbs to generate a panel of CAR(+) T cells. While all CARs exhibited specificity to CD123, one V-H and V-L combination had reduced lysis of normal hematopoietic stem cells. This CAR's in vivo anti-tumor activity was similar whether signaling occurred via chimeric CD28 or CD137, prolonging survival in both AML and ALL models. Co-expression of inducible caspase 9 eliminated CAR(+) T cells. These data help support the use of CD123-specific CARs for treatment of CD123(+) hematologic malignancies.
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