title: Adoptive immunotherapy for advanced non-small cell lung cancer using zoledronate-expanded γδTcells: a phase I clinical study.
abstract: Human γδ T cells can recognize and kill non-small cell lung cancer (NSCLC) cells using the Vγ9Vδ2 T-cell receptor and/or NKG2D. We have established clinical grade large-scale ex vivo expansion of γδ T cells from peripheral blood mononuclear cells by culturing with zoledronate and interleukin-2 (IL-2). A phase I study was conducted to evaluate safety and potential antitumor effects of re-infusing ex vivo expanded γδ T cells in patients with recurrent or advanced NSCLC. Patient's peripheral blood mononuclear cells were stimulated with zoledronate (5 μM) and IL-2 (1000 IU/mL) for 14 days. Harvested cells, mostly γδ T cells, were given intravenously every 2 weeks without additional IL-2, a total of 6 times. The cumulative number of transferred γδ T cells ranged from 2.6 to 45.1 x 10⁹ (median, 15.7×10⁹). Fifteen patients underwent adoptive immunotherapy with these γδ T cells. There were no severe adverse events related to the therapy. Immunomonitoring data showed that with increasing numbers of infusions, the number of peripheral γδ T cells gradually increased. All patients remained alive during the study period with a median survival of 589 days and median progression-free survival of 126 days. According to the Response Evaluation Criteria In Solid Tumors, there were no objective responses. Six patients had stable disease, whereas the remaining 6 evaluable patients experienced progressive disease 4 weeks after the sixth transfer. We conclude that adoptive transfer of zoledronate-expanded γδ T cells is safe and feasible in patients with NSCLC, refractory to other treatments.
authors.affiliation: Departments of Immunotherapeutics (Medinet), The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Sakamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Nakajima
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Murakawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukami
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Tomonori
authors.initials: T
authors.lastname: Murayama
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takamoto
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsushita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kakimi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011788:Quality of Life; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D007376:Interleukin-2; D000077211:Zoledronic Acid