Combination Treatment of Murine Tumors by Adenovirus-Mediated Local B7/IL12 Immunotherapy and Radiotherapy

Failure of local tumor control still poses a problem for radiotherapy and translates into reduced survival. Combining radiation with chemotherapy or other newer modalities has shown promising results. Immunological approaches to tumor therapy have found renewed interest due to improved insight into...

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Bibliographic Details
Published in:Molecular therapy 2000-09, Vol.2 (3), p.195-203
Main Authors: Lohr, Frank, Hu, Kang, Haroon, Zishan, Samulski, Thaddeus V., Huang, Qian, Beaty, Jennifer, Dewhirst, Mark W., Li, Chuan-Yuan
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Adenoviruses
Animals
B7-1 Antigen - administration & dosage
B7-1 Antigen - genetics
Cell culture
costimulatory molecules
Cytokines
Cytomegalovirus
Dose Fractionation
Flow cytometry
Gene Expression
Gene therapy
IL12
Immunotherapy
Infections
interleukin 12
Interleukin-12 - administration & dosage
Interleukin-12 - genetics
Killer Cells, Natural - immunology
Metastasis
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
multi-modality therapy
Neoplasms, Experimental - immunology
Neoplasms, Experimental - radiotherapy
Neoplasms, Experimental - therapy
Oncology
Radiation therapy
radiotherapy
T-Lymphocytes, Cytotoxic - immunology
Toxicity
Tumors
Viruses
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Summary:Failure of local tumor control still poses a problem for radiotherapy and translates into reduced survival. Combining radiation with chemotherapy or other newer modalities has shown promising results. Immunological approaches to tumor therapy have found renewed interest due to improved insight into mechanisms involved in the immune response to tumors. In this paper, we studied tumor growth delay after various combination regimens of locally injected adenovirus constitutively expressing IL12 and B7.1 (AdIL12/B7.1) and fractionated radiotherapy in two nonimmunogenic murine tumor models, 4T1 and B16.F10. Effects of radiation and virus infection on surface antigen expression in these tumor lines were assessed. Mechanisms of action of AdIL12/B7.1 were studied by conducting additional experiments with and without depletion of NK-cells and/or T-cells, and by cytotoxic T-lymphocyte assays, and immunohistochemical evaluation of tumor blood vessels. Both B7.1 and IL12 were effectively expressed in both irradiated and unirradiated 4T1 and B16.F10 tumor cells but did not add significantly to radiation-induced cell killing in vitro. However, local tumor infection by AdIL12/B7.1 after irradiation significantly increases the effectiveness of radiotherapy when applied after completion of radiotherapy. The mechanism appears to be complicated, involving a host of factors that included the ability of IL12 to activate T-cells and NK-cells and to inhibit angiogenesis and the ability of radiation to induce apoptosis or necrosis among tumor cells. These data support the combination of radiotherapy with adenovirus-mediated immunotherapy and suggest that the concept of adding genetic immunotherapy after radiotherapy in a combined regimen merits further study.
ISSN:1525-0016
1525-0024
DOI:10.1006/mthe.2000.0114