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Author Benaduce, Ana Paula ♦ Brenneman, Randall ♦ Schrand, Brett ♦ Pollack, Alan ♦ Gilboa, Eli ♦ Ishkanian, Adrian
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword RADIOLOGY AND NUCLEAR MEDICINE ♦ FRACTIONATED IRRADIATION ♦ GY RANGE 01-10 ♦ GY RANGE 10-100 ♦ LIVER ♦ MAMMARY GLANDS ♦ MONOCLONAL ANTIBODIES ♦ NEOPLASMS ♦ RADIATION DOSES ♦ RADIOTHERAPY
Abstract Purpose: To report a novel strategy using oligonucleotide aptamers to 4-1BB as an alternate method for costimulation, and show that combinatorial therapy with radiation improves the therapeutic ratio over equivalent monoclonal antibodies. Methods and Materials: Subcutaneous 4T1 (mouse mammary carcinoma) tumors were established (approximately 100 mm{sup 3}), and a radiation therapy (RT) dose/fractionation schedule that optimally synergizes with 4-1BB monoclonal antibody (mAb) was identified. Comparable tumor control and animal survival was observed when either 4-1BB antibody or aptamer were combined with RT using models of breast cancer and melanoma (4T1 and B16-F10). Off-target CD8{sup +} T-cell toxicity was evaluated by quantification of CD8{sup +} T cells in livers and spleens of treated animals. Results: When combined with 4-1BB mAb, significant differences in tumor control were observed by varying RT dose and fractionation schedules. Optimal synergy between RT and 4-1BB mAb was observed at 5 Gy × 6. Testing 4-1BB mAb and aptamer independently using the optimal RT (5 Gy × 6 for 4T1/Balb/c and 12 Gy × 1 for B16/C57BL6J mouse models) revealed equivalent tumor control using 4-1BB aptamer and 4-1BB mAb. 4-1BB mAb, but not 4-1BB aptamer-treated animals, exhibited increased lymphocytic liver infiltrates and increased splenic and liver CD8{sup +} T cells. Conclusions: Radiation therapy synergizes with 4-1BB mAb, and this effect is dependent on RT dose and fractionation. Tumor control by 4-1BB aptamer is equivalent to 4-1BB mAb when combined with optimal RT dose, without eliciting off-target liver and spleen CD8{sup +} expansion. 4-1BB aptamer-based costimulation affords a comparable and less toxic strategy to augment RT-mediated tumor control.
ISSN 03603016
Educational Use Research
Learning Resource Type Article
Publisher Date 2016-10-01
Publisher Place United States
Journal International Journal of Radiation Oncology, Biology and Physics
Volume Number 96
Issue Number 2


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