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Introduction: CD3 [gamma][delta] T cells comprise 2% to 5% of circulating T cells with V[gamma]9V[delta]2 cells the dominant circulating subtype. V[gamma]9V[delta]2 cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of [gamma][delta] T cells represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB). In this prospective, non-randomized Phase I trial, we assessed whether circulating V[gamma]9V[delta]2 cells could be safely expanded using intravenous ZOL (Zoledronate [Zometa(R)]) and subcutaneous Interleukin-2 (IL-2) in patients with refractory NB.

Methods: Patients 2 to 21 years of age with refractory neuroblastoma with no known curative therapeutic options received ZOL on day 1, and IL-2 on days 1 to 5 and 15 to 19 of each 28-day cycle (n = 4). Lymphocyte immunophenotyping was assessed weekly. Immunophenotyping studies from the treatment group were compared with healthy pediatric controls (n = 16; range, 5y-15y) and of untreated NB disease controls (n = 9; range, 4m-18y).

Results: Treatment was well tolerated with no unexpected grade 3 and 4 toxicities. Lymphocyte subset counts did not differ significantly between volunteers and disease controls with the exception of [gamma][delta] T cell counts that were significantly higher in healthy volunteers (212 93 vs. 89 42, P = 0.05). Study patients showed increases in circulating [gamma][delta] T cell count (3-10 fold) after the first week, increasing into the range seen in healthy volunteers (125 37, P = 0.1940). Interestingly, all ZOL IL-2 treated patients showed significant increases in CD3 CD4 CD27hiCD127dim T cells that rose weekly in 2 patients throughout the 4 weeks of observation (maximum 41% and 24% of total CD3 CD4 T cells, respectively).

Conclusions: In summary, combined ZOL and IL-2 is well tolerated and restored [gamma][delta] T cell counts to the normal range with a moderate expansion of Natural Killer cells. Progressive increases in circulating CD4 T cells with a regulatory phenotype cells may offset beneficial effects of this therapy.

Copyright (C) 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.