Journal
BLOOD
Volume 117, Issue 18, Pages 4736-4745Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-10-311845
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Funding
- Leukemia & Lymphoma Society Specialized Center of Research (SCOR) [7018]
- National Institutes of Health [P01CA94237, P50CA126752]
- Leukemia & Lymphoma Society
- Doris Duke Charitable Foundation/Clinical Scientist Development
- Associazione Italiana per la Ricerca sul cancro (AIRC)
- Ferrero Foundation (Alba, Italy)
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Chronic lymphocytic leukemia (CLL) is characterized by an accumulation of mature CD19(+)CD5(+)CD20(dim) B lymphocytes that typically express the B-cell activation marker CD23. In the present study, we cloned and expressed in T lymphocytes a novel chimeric antigen receptor (CAR) targeting the CD23 antigen (CD23. CAR). CD23.CAR(+) T cells showed specific cytotoxic activity against CD23(+) tumor cell lines (average lysis 42%) and primary CD23(+) CLL cells (average lysis 58%). This effect was obtained without significant toxicity against normal B lymphocytes, in contrast to CARs targeting CD19 or CD20 antigens, which are also expressed physiologically by normal B lymphocytes. Moreover, CLL-derived CD23.CAR(+) T cells released inflammatory cytokines (1445-fold more TNF-beta, 20-fold more TNF-alpha, and 4-fold more IFN-gamma). IL-2 was also produced (average release 2681 pg/mL) and sustained the antigen-dependent proliferation of CD23.CAR(+) T cells. Redirected T cells were also effective in vivo in a CLL Rag2(-/-)gamma(-/-)(c) xenograft mouse model. Compared with mice treated with control T cells, the infusion of CD23. CAR(+) T cells resulted in a significant delay in the growth of the MEC-1 CLL cell line. These data suggest that CD23. CAR(+) T cells represent a selective immunotherapy for the elimination of CD23(+) leukemic cells in patients with CLL. (Blood. 2011; 117(18): 4736-4745)
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