4-1BB aptamer based immunomodulation enhances the therapeutic index of radiotherapy in murine tumor models

Publication date: Available online 21 May 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ana Paula Benaduce, Randall Brenneman, Brett Schrand, Alan Pollack, Eli Gilboa, Adrian Ishkanian
PurposeThere is growing evidence to suggest checkpoint blockade immunotherapy such as Ipilimumab and Nivolumab can significantly improve radiation induced solid tumor control. Preclinical data suggests that combining co-stimulatory agents with checkpoint blockade and radiation will significantly improve responses. However, clinical translation of co-stimulatory antibodies, such as 4-1BB, have been hindered by dose limiting toxicity. We report a novel strategy using oligonucleotide aptamers to 4-1BB as an alternate method for co-stimulation, and show combinatorial therapy with radiation improves the therapeutic ratio over equivalent monoclonal antibodies.Methods & MaterialsSubcutaneous 4T1 (mouse mammary carcinoma) tumors were established (∼100 mm³) and an RT dose/fractionation schedule that optimally synergizes with 4-1BB 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.ResultsWhen 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 5Gyx6. Testing 4-1BB mAb and aptamer independently using the optimal RT (5Gyx6 for 4T1/Balb/c and 12Gyx1 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.ConclusionsRT 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.

Teaser

Off-target toxicity of co-stimulatory mAbs such as 4-1BB hinders their clinical translation. Combining RT with 4-1BB aptamer or 4-1BB mAb therapy exhibited equivalent tumor control in murine tumor models. 4-1BB aptamer treatment did not promote CD8+ T cell liver and spleen infiltration, suggesting a superior therapeutic index over mAb. This study provides preliminary rationale for development of costimulatory aptamers as a complementary strategy for combination with RT and existing checkpoint blockade mAbs.


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