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

Miran Blanchard, Kevin G. Shim, Michael P. Grams, Karishma Rajani, Rosa M. Diaz, Keith M. Furutani, Jill Thompson, Kenneth R. Olivier, Sean S Park, Svetomir Nenad Markovic, Hardev Pandha, Alan Melcher, Kevin Harrington, Shane Zaidi, Richard Geoffrey Vile

Research output: Contribution to journalArticle

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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. 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.

Original languageEnglish (US)
Pages (from-to)577-587
Number of pages11
JournalInternational Journal of Radiation Oncology Biology Physics
Volume93
Issue number3
DOIs
StatePublished - Nov 1 2015

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Immunotherapy
Vesicular Stomatitis
radiation therapy
Melanoma
Radiotherapy
tumors
viruses
Neoplasm Antigens
antigens
Viruses
Neoplasms
T-Lymphocytes
mice
therapy
Viral Tumor Antigens
Complementary Therapies
Intravenous Administration
clearing
chemotherapy
Antigens

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation
  • Cancer Research

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Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy. / Blanchard, Miran; Shim, Kevin G.; Grams, Michael P.; Rajani, Karishma; Diaz, Rosa M.; Furutani, Keith M.; Thompson, Jill; Olivier, Kenneth R.; Park, Sean S; Markovic, Svetomir Nenad; Pandha, Hardev; Melcher, Alan; Harrington, Kevin; Zaidi, Shane; Vile, Richard Geoffrey.

In: International Journal of Radiation Oncology Biology Physics, Vol. 93, No. 3, 01.11.2015, p. 577-587.

Research output: Contribution to journalArticle

Blanchard, M, Shim, KG, Grams, MP, Rajani, K, Diaz, RM, Furutani, KM, Thompson, J, Olivier, KR, Park, SS, Markovic, SN, Pandha, H, Melcher, A, Harrington, K, Zaidi, S & Vile, RG 2015, 'Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy', International Journal of Radiation Oncology Biology Physics, vol. 93, no. 3, pp. 577-587. https://doi.org/10.1016/j.ijrobp.2015.07.2274
Blanchard, Miran ; Shim, Kevin G. ; Grams, Michael P. ; Rajani, Karishma ; Diaz, Rosa M. ; Furutani, Keith M. ; Thompson, Jill ; Olivier, Kenneth R. ; Park, Sean S ; Markovic, Svetomir Nenad ; Pandha, Hardev ; Melcher, Alan ; Harrington, Kevin ; Zaidi, Shane ; Vile, Richard Geoffrey. / Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy. In: International Journal of Radiation Oncology Biology Physics. 2015 ; Vol. 93, No. 3. pp. 577-587.
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AU - Blanchard, Miran

AU - Shim, Kevin G.

AU - Grams, Michael P.

AU - Rajani, Karishma

AU - Diaz, Rosa M.

AU - Furutani, Keith M.

AU - Thompson, Jill

AU - Olivier, Kenneth R.

AU - Park, Sean S

AU - Markovic, Svetomir Nenad

AU - Pandha, Hardev

AU - Melcher, Alan

AU - Harrington, Kevin

AU - Zaidi, Shane

AU - Vile, Richard Geoffrey

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