title: Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells.
abstract: Multiple myeloma causes approximately 10% of all hematologic malignancies. We have previously shown that human T cells expressing chimeric NKG2D receptors (chNKG2D) consisting of NKG2D fused to the CD3ζ cytoplasmic domain secrete proinflammatory cytokines and kill human myeloma cells. In this study, we show chNKG2D T cells are effective in a murine model of multiple myeloma. Mice with established 5T33MM-green fluorescent protein tumors were treated with one or two infusions of chNKG2D T cells. Compared with mice treated with T cells expressing wild type (wt)NKG2D receptors, a single dose of chNKG2D T cells increased survival, with half of the chNKG2D T-cell-treated mice surviving long term. Two infusions of chNKG2D T cells led to tumor-free survival in all mice. ChNKG2D T cells were located at sites of tumor growth, including the bone marrow and spleen after intravenous injection. There was an increase in activated host T cells and NK cells at tumor sites and in serum interferon-γ after chNKG2D T-cell injection. Surviving mice were able to resist a rechallenge with 5T33MM cells but not RMA lymphoma cells, indicating that the mice developed a protective, specific memory response. These data demonstrate that chNKG2D T cells may be an effective adoptive cellular therapy for multiple myeloma.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: A
authors.initials: A
authors.lastname: Barber
authors.forename: K R
authors.initials: KR
authors.lastname: Meehan
authors.forename: C L
authors.initials: CL
authors.lastname: Sentman
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics*; D004195:Disease Models, Animal; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D019076:Transgenes
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D055655:NK Cell Lectin-Like Receptor Subfamily K; D007371:Interferon-gamma