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Title: Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy

Abstract

Purpose: 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 and Materials: 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.more » 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.« less

Authors:
 [1];  [1];  [2]; ;  [1];  [2];  [1]; ;  [2];  [3];  [4];  [5];  [6];  [1];  [1]
  1. Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota (United States)
  2. Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)
  3. Department of Immunology, Mayo Clinic, Rochester, Minnesota (United States)
  4. The Postgraduate Medical School, University of Surrey, Guildford (United Kingdom)
  5. Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds (United Kingdom)
  6. Targeted Therapy Laboratory, The Institute of Cancer Research, London (United Kingdom)
Publication Date:
OSTI Identifier:
22644981
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 93; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CHEMOTHERAPY; IMMUNOTHERAPY; MELANOMAS; RADIOTHERAPY

Citation Formats

Blanchard, Miran, Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, Shim, Kevin G., Department of Immunology, Mayo Clinic, Rochester, Minnesota, Grams, Michael P., Rajani, Karishma, Diaz, Rosa M., Furutani, Keith M., Thompson, Jill, Olivier, Kenneth R., Park, Sean S., Markovic, Svetomir N., Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, Pandha, Hardev, Melcher, Alan, Harrington, Kevin, Zaidi, Shane, Targeted Therapy Laboratory, The Institute of Cancer Research, London, Vile, Richard, Department of Immunology, Mayo Clinic, Rochester, Minnesota, and Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds. Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy. United States: N. p., 2015. Web. doi:10.1016/J.IJROBP.2015.07.2274.
Blanchard, Miran, Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, Shim, Kevin G., Department of Immunology, Mayo Clinic, Rochester, Minnesota, Grams, Michael P., Rajani, Karishma, Diaz, Rosa M., Furutani, Keith M., Thompson, Jill, Olivier, Kenneth R., Park, Sean S., Markovic, Svetomir N., Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, Pandha, Hardev, Melcher, Alan, Harrington, Kevin, Zaidi, Shane, Targeted Therapy Laboratory, The Institute of Cancer Research, London, Vile, Richard, Department of Immunology, Mayo Clinic, Rochester, Minnesota, & Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds. Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy. United States. https://doi.org/10.1016/J.IJROBP.2015.07.2274
Blanchard, Miran, Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, Shim, Kevin G., Department of Immunology, Mayo Clinic, Rochester, Minnesota, Grams, Michael P., Rajani, Karishma, Diaz, Rosa M., Furutani, Keith M., Thompson, Jill, Olivier, Kenneth R., Park, Sean S., Markovic, Svetomir N., Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, Pandha, Hardev, Melcher, Alan, Harrington, Kevin, Zaidi, Shane, Targeted Therapy Laboratory, The Institute of Cancer Research, London, Vile, Richard, Department of Immunology, Mayo Clinic, Rochester, Minnesota, and Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds. 2015. "Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy". United States. https://doi.org/10.1016/J.IJROBP.2015.07.2274.
@article{osti_22644981,
title = {Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy},
author = {Blanchard, Miran and Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota and Shim, Kevin G. and Department of Immunology, Mayo Clinic, Rochester, Minnesota and Grams, Michael P. and Rajani, Karishma and Diaz, Rosa M. and Furutani, Keith M. and Thompson, Jill and Olivier, Kenneth R. and Park, Sean S. and Markovic, Svetomir N. and Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota and Pandha, Hardev and Melcher, Alan and Harrington, Kevin and Zaidi, Shane and Targeted Therapy Laboratory, The Institute of Cancer Research, London and Vile, Richard and Department of Immunology, Mayo Clinic, Rochester, Minnesota and Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds},
abstractNote = {Purpose: 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 and Materials: 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.},
doi = {10.1016/J.IJROBP.2015.07.2274},
url = {https://www.osti.gov/biblio/22644981}, journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 3,
volume = 93,
place = {United States},
year = {Sun Nov 01 00:00:00 EDT 2015},
month = {Sun Nov 01 00:00:00 EDT 2015}
}