title: Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy.
abstract: OBJECTIVE
  The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responses capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease.
  
  
  METHODS
  We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease.
  
  
  RESULTS
  Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV-TAA, might contribute to control of local and systemic disease. In addition, VSV-TAA therapy alone had significant effects on control of both local and metastatic tumors.
  
  
  CONCLUSIONS
  We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary combination therapy model that addresses the need for both systemic and local control in oligometastatic melanoma.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Miran
authors.initials: M
authors.lastname: Blanchard
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota; Department of Immunology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Shim
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Grams
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Karishma
authors.initials: K
authors.lastname: Rajani
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Diaz
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Furutani
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Jill
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Olivier
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Sean S
authors.initials: SS
authors.lastname: Park
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota; Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.affiliation: The Postgraduate Medical School, University of Surrey, Guildford, United Kingdom.
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Melcher
authors.affiliation: Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota; Targeted Therapy Laboratory, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Shane
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota; Department of Immunology, Mayo Clinic, Rochester, Minnesota; Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, United Kingdom. Electronic address: vile.richard@mayo.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Vile
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D003131:Combined Modality Therapy / Q000379:methods; D007111:Immunity, Cellular; D007121:Immunocompetence; D007167:Immunotherapy / Q000379:methods*; D007275:Injections, Intravenous; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation / Q000379:methods; D050130:Oncolytic Virotherapy / Q000379:methods*; D016634:Radiosurgery / Q000379:methods*; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology*; D018116:Vesiculovirus / Q000276:immunology*; D014916:Whole-Body Irradiation
chemical_list: D000951:Antigens, Neoplasm