细胞毒性
体内
癌症研究
归巢(生物学)
免疫疗法
医学
淋巴因子激活杀伤细胞
K562细胞
免疫学
转移
自然杀伤细胞
骨肉瘤
白细胞介素21
体外
病理
生物
内科学
免疫系统
T细胞
癌症
白血病
生态学
生物化学
生物技术
作者
Robert J. Canter,Steven K. Grossenbacher,Jennifer A. Foltz,Ian R. Sturgill,Jiwon S. Park,Jesus I. Luna,Michael S. Kent,William T. N. Culp,Mingyi Chen,Jaime F. Modiano,Arta M. Monjazeb,Dean Lee,William J. Murphy
标识
DOI:10.1186/s40425-017-0305-7
摘要
We have previously shown that radiotherapy (RT) augments natural killer (NK) functions in pre-clinical models of human and mouse cancers, including sarcomas. Since dogs are an excellent outbred model for immunotherapy studies, we sought to assess RT plus local autologous NK transfer in canine sarcomas.Dog NK cells (CD5dim, NKp46+) were isolated from PBMCs and expanded with irradiated K562-C9-mIL21 feeder cells and 100 IU/mL recombinant human IL-2. NK homing and cytotoxicity ± RT were evaluated using canine osteosarcoma tumor lines and dog patient-derived xenografts (PDX). In a first-in-dog clinical trial for spontaneous osteosarcoma, we evaluated RT and intra-tumoral autologous NK transfer.After 14 days, mean NK expansion and yield were 19.0-fold (±8.6) and 258.9(±76.1) ×106 cells, respectively. Post-RT, NK cytotoxicity increased in a dose-dependent fashion in vitro reaching ~ 80% at effector:target ratios of ≥10:1 (P < 0.001). In dog PDX models, allogeneic NK cells were cytotoxic in ex vivo killing assays and produced significant PDX tumor growth delay (P < 0.01) in vivo. After focal RT and intravenous NK transfer, we also observed significantly increased NK homing to tumors in vivo. Of 10 dogs with spontaneous osteosarcoma treated with focal RT and autologous NK transfer, 5 remain metastasis-free at the 6-month primary endpoint with resolution of suspicious pulmonary nodules in one patient. We also observed increased activation of circulating NK cells after treatment and persistence of labelled NK cells in vivo.NK cell homing and cytotoxicity are increased following RT in canine models of sarcoma. Results from a first-in-dog clinical trial are promising, including possible abscopal effects.
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