TY - JOUR
T1 - Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy
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 N.
AU - Pandha, Hardev
AU - Melcher, Alan
AU - Harrington, Kevin
AU - Zaidi, Shane
AU - Vile, Richard
N1 - Funding Information:
We thank Toni Higgins for expert secretarial assistance. This work was funded by The Richard M. Schulze Family Foundation , the Mayo Foundation , Cancer Research UK , the National Institutes of Health (Grants R01CA107082 , R01CA130878 , R01CA132734 , and R01CA175386-01A1 ), the European Research Council , the University of Leeds , the University of Minnesota / Mayo Foundation Partnership (MNP#14.14) , and a grant from Terry and Judith Paul . K.J.H. received support from the ICR/RM NIHR Biomedical Research Centre.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ijrobp.2015.07.2274
DO - 10.1016/j.ijrobp.2015.07.2274
M3 - Article
C2 - 26461000
AN - SCOPUS:84942306019
SN - 0360-3016
VL - 93
SP - 577
EP - 587
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 3
ER -