Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial
Abstract Background 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 trans...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2017-12-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-017-0305-7 |
| _version_ | 1818293219947970560 |
|---|---|
| author | 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 A. Lee William J. Murphy |
| author_facet | 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 A. Lee William J. Murphy |
| author_sort | Robert J. Canter |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| first_indexed | 2024-12-13T03:12:23Z |
| format | Article |
| id | doaj.art-d9d90a18101e43b28f38e4ccfff5995e |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-13T03:12:23Z |
| publishDate | 2017-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-d9d90a18101e43b28f38e4ccfff5995e2022-12-22T00:01:34ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262017-12-015111610.1186/s40425-017-0305-7Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trialRobert J. Canter0Steven K. Grossenbacher1Jennifer A. Foltz2Ian R. Sturgill3Jiwon S. Park4Jesus I. Luna5Michael S. Kent6William T. N. Culp7Mingyi Chen8Jaime F. Modiano9Arta M. Monjazeb10Dean A. Lee11William J. Murphy12Department of Surgery, Division of Surgical Oncology, University of California Davis Medical CenterLaboratory of Cancer Immunology, Department of Dermatology, University of California Davis Medical CenterNationwide Children’s Hospital, Center for Childhood Cancer & Blood DiseasesLaboratory of Cancer Immunology, Department of Dermatology, University of California Davis Medical CenterDepartment of Surgery, University of California Davis Medical CenterLaboratory of Cancer Immunology, Department of Dermatology, University of California Davis Medical CenterThe Center for Companion Animal Health, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-DavisThe Center for Companion Animal Health, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-DavisDepartment of Pathology and Laboratory Medicine, UT Southwestern Medical CenterDepartment of Veterinary Clinical Sciences, College of Veterinary Medicine, Animal Cancer Care and Research Center, Center for Immunology, Masonic Cancer Center, and Stem Cell Institute, University of MinnesotaDepartment of Radiation Oncology, University of California Davis Medical CenterNationwide Children’s Hospital, Center for Childhood Cancer & Blood DiseasesDepartments of Dermatology and Internal Medicine, University of California Davis Medical CenterAbstract Background 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. Methods 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. Results 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. Conclusions 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.http://link.springer.com/article/10.1186/s40425-017-0305-7Natural killer cellsAdoptive immunotherapyRadiotherapySarcomaCanine |
| spellingShingle | 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 A. Lee William J. Murphy Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial Journal for ImmunoTherapy of Cancer Natural killer cells Adoptive immunotherapy Radiotherapy Sarcoma Canine |
| title | Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial |
| title_full | Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial |
| title_fullStr | Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial |
| title_full_unstemmed | Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial |
| title_short | Radiotherapy enhances natural killer cell cytotoxicity and localization in pre-clinical canine sarcomas and first-in-dog clinical trial |
| title_sort | radiotherapy enhances natural killer cell cytotoxicity and localization in pre clinical canine sarcomas and first in dog clinical trial |
| topic | Natural killer cells Adoptive immunotherapy Radiotherapy Sarcoma Canine |
| url | http://link.springer.com/article/10.1186/s40425-017-0305-7 |
| work_keys_str_mv | AT robertjcanter radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT stevenkgrossenbacher radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT jenniferafoltz radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT ianrsturgill radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT jiwonspark radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT jesusiluna radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT michaelskent radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT williamtnculp radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT mingyichen radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT jaimefmodiano radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT artammonjazeb radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT deanalee radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial AT williamjmurphy radiotherapyenhancesnaturalkillercellcytotoxicityandlocalizationinpreclinicalcaninesarcomasandfirstindogclinicaltrial |