title: Pilot trial of interleukin-2 and zoledronic acid to augment γδ T cells as treatment for patients with refractory renal cell carcinoma.
abstract: Prior to the advent of VEGF-targeted therapies, renal cell carcinoma (RCC) was among the few solid tumors shown to respond to cytokine-based therapies such as interleukin-2 (IL-2) and interferon alpha. Previous work has shown that aminobisphosphonates, including zoledronic acid (ZA), are capable of activating human Vγ9 Vδ2 T cells in vitro, and these cells can be further expanded with IL-2. Moreover, these Vγ9 Vδ2 T cells have cytolytic activity in vitro to multiple human tumor cell lines. In the current report, we have conducted a pilot trial in patients with metastatic RCC, evaluating different doses of ZA in combination with low-dose IL-2 to determine whether combining these agents can promote in vivo proliferation of Vγ9 Vδ2 T cells and elicit an antitumor response. In 12 patients evaluated, no objective clinical responses were observed by RECIST criteria; however, two patients experienced prolonged stable disease. A modest increase in Vγ9 Vδ2 T-cell frequency could be detected by Day 8 of therapy in four of the nine patients who received at least one cycle of therapy, but not to the magnitude anticipated from preclinical models. Repeated administration of IL-2 and ZA resulted in both a diminished in vivo percentage of Vγ9 Vδ2 T cells as well as impaired expansion in vitro after the first cycle of therapy. These results suggest that repeated administration of IL-2 and ZA, at the doses and schedules used in this trial, may actually inhibit the proliferative capacity of Vγ9 Vδ2 T cell in patients with metastatic RCC.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Wisconsin, Madison, WI, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Lang
authors.forename: Mahazarin R
authors.initials: MR
authors.lastname: Kaikobad
authors.forename: Marianne
authors.initials: M
authors.lastname: Wallace
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Staab
authors.forename: Dorothea L
authors.initials: DL
authors.lastname: Horvath
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.forename: Jens C
authors.initials: JC
authors.lastname: Eickhoff
authors.forename: Douglas G
authors.initials: DG
authors.lastname: McNeel
authors.forename: Miroslav
authors.initials: M
authors.lastname: Malkovsky
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D002469:Cell Separation; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000628:therapy*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D007376:Interleukin-2; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid