4-1BB Aptamer-Based Immunomodulation Enhances the Therapeutic Index of Radiation Therapy in Murine Tumor Models

Ana Paula Benaduce, Randall Brenneman, Brett Schrand, Alan Pollack, Eli Gilboa, Adrian Ishkanian

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 mm3), 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+ T-cell toxicity was evaluated by quantification of CD8+ 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+ 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+ expansion. 4-1BB aptamer-based costimulation affords a comparable and less toxic strategy to augment RT-mediated tumor control.

Original languageEnglish (US)
Pages (from-to)458-461
Number of pages4
JournalInternational Journal of Radiation Oncology Biology Physics
Volume96
Issue number2
DOIs
StatePublished - Oct 1 2016

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Immunomodulation
antibodies
radiation therapy
Radiotherapy
tumors
Monoclonal Antibodies
Neoplasms
Dose Fractionation
liver
fractionation
animals
Therapeutics
dosage
spleen
Liver
Breast Neoplasms
schedules
T-Lymphocytes
mice
Appointments and Schedules

ASJC Scopus subject areas

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

Cite this

4-1BB Aptamer-Based Immunomodulation Enhances the Therapeutic Index of Radiation Therapy in Murine Tumor Models. / Benaduce, Ana Paula; Brenneman, Randall; Schrand, Brett; Pollack, Alan; Gilboa, Eli; Ishkanian, Adrian.

In: International Journal of Radiation Oncology Biology Physics, Vol. 96, No. 2, 01.10.2016, p. 458-461.

Research output: Contribution to journalArticle

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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 mm3), 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+ T-cell toxicity was evaluated by quantification of CD8+ 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+ 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+ expansion. 4-1BB aptamer-based costimulation affords a comparable and less toxic strategy to augment RT-mediated tumor control.",
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