title: In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor.
abstract: 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-β, 20-fold more TNF-α, and 4-fold more IFN-γ). 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(-/-)γ(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.
authors.affiliation: Department of Pediatrics, University of Milano-Bicocca, Milan, Italy.
authors.forename: Greta Maria Paola
authors.initials: GM
authors.lastname: Giordano Attianese
authors.forename: Virna
authors.initials: V
authors.lastname: Marin
authors.forename: Valentina
authors.initials: V
authors.lastname: Hoyos
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: Irene
authors.initials: I
authors.lastname: Pizzitola
authors.forename: Sarah
authors.initials: S
authors.lastname: Tettamanti
authors.forename: Valentina
authors.initials: V
authors.lastname: Agostoni
authors.forename: Matteo
authors.initials: M
authors.lastname: Parma
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Maria T S
authors.initials: MT
authors.lastname: Bertilaccio
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Ettore
authors.initials: E
authors.lastname: Biagi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000096:biosynthesis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000628:therapy*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D017455:Receptors, IgE / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C508594:IL2 protein, human; D007376:Interleukin-2; C499308:Rag2 protein, mouse; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins