title: Anti-leukemia activity of in vitro-expanded human gamma delta T cells in a xenogeneic Ph+ leukemia model.
abstract: Gamma delta T cells (GDTc) lyse a variety of hematological and solid tumour cells in vitro and in vivo, and are thus promising candidates for cellular immunotherapy. We have developed a protocol to expand human GDTc in vitro, yielding highly cytotoxic Vgamma9/Vdelta2 CD27/CD45RA double negative effector memory cells. These cells express CD16, CD45RO, CD56, CD95 and NKG2D. Flow cytometric, clonogenic, and chromium release assays confirmed their specific cytotoxicity against Ph(+) cell lines in vitro. We have generated a fluorescent and bioluminescent Ph(+) cell line, EM-2eGFPluc, and established a novel xenogeneic leukemia model. Intravenous injection of EM-2eGFPluc into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice resulted in significant dose-dependent bone marrow engraftment; lower levels engrafted in blood, lung, liver and spleen. In vitro-expanded human GDTc injected intraperitoneally were found at higher levels in blood and organs compared to those injected intravenously; GDTc survived at least 33 days post-injection. In therapy experiments, we documented decreased bone marrow leukemia burden in mice treated with GDTc. Live GDTc were found in spleen and bone marrow at endpoint, suggesting the potential usefulness of this therapy.
authors.affiliation: Cell Therapy Program, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada. gsiegers@imaging.robarts.ca
authors.forename: Gabrielle M
authors.initials: GM
authors.lastname: Siegers
authors.forename: Tania C
authors.initials: TC
authors.lastname: Felizardo
authors.forename: A Mark
authors.initials: AM
authors.lastname: Mathieson
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kosaka
authors.forename: Xing-Hua
authors.initials: XH
authors.lastname: Wang
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Medin
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010677:Philadelphia Chromosome; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000502:physiology / Q000637:transplantation*; D014183:Transplantation, Heterologous
chemical_list: D016692:Receptors, Antigen, T-Cell, gamma-delta