Abstract 4712: Image-guided focal irradiation in syngeneic preclinical oncology mouse models
Authors: Krueger Sarah , Dailey Thomas , Guley Kevin , Franklin Maryland 
Published: July 2017

Use of image-guided focal irradiation is a mainstay of human cancer treatment. Image guidance allows for highly conformal treatment plans that minimize normal tissue toxicity and systemic response. With the advent of image-guided small animal irradiators such as the Small Animal Radiation Research Platform (SARRP), targeted focal irradiation can now be utilized in a broad range of preclinical oncology models. Of particular interest is the possible use of focal irradiation to broaden the efficacy and response duration of immuno-oncology therapy. The work presented here evaluates tumor response in a number of syngeneic tumor models following focal irradiation alone and in combination with immune regulation.

Image-guided irradiation was performed using a SARRP system (Xstrahl Inc., Suwanee, GA). Animals were imaged with an open field at 60 kV and 0.5 mA for a computed tomography (CT) image which was used for treatment planning. Treatment was delivered at 220 kV and 13.0 mA using an appropriately sized collimator to the total indicated dose (in Gray; Gy) in 2 equally weighted beams. For daily treatments, the same treatment plan was applied and adjusted for changes in animal positioning or target alteration over time. Bilateral subcutaneous (SC) mouse tumor models tested were A20 (B cell lymphoma; Balb/C mice) and RIF1 (sarcoma; C3H mice) and an intracranial (IC) GL261-luc (glioblastoma; C57BL/6 mice) model.

In the SC models, focal irradiation was delivered only to the right side tumors and tumor growth changes tracked for both right and left side implants. A20 was sensitive to both fractionated low doses (2.5Gy) of radiation, which resulted in tumor stasis, and single bolus 20Gy, which resulted in tumor regressions. Effects on the non-irradiated left sides were dependent upon which dose regimen was utilized. RIF1 is a more radiation resistant model and a single bolus dose of 10Gy only moderately reduced tumor burden on the right side tumors but had no effect on the contralateral tumors. In the GL261-luc IC model a single bolus dose of 15Gy was curative whereas 10Gy resulted in 60-75% mortality over the study duration. In a follow on study we determined that combination of 10Gy focal radiation with systemic anti-PD-1 antibody therapy could improve overall survival over either monotherapy.

In mouse models, radiation treatment has been shown to increase the level of tumor antigen presentation and the variety of peptides available for cross-presentation. Current work in the field focuses on using radiation as a tool to bridge the gap from tumor equilibrium to tumor elimination, which could improve the response rate of immuno-oncology agents. The models presented here highlight the importance in choosing appropriate focal irradiation targets, dose regimens and timing for each model. Tools such as the SARRP greatly enhance the ability of preclinical models to provide a first line assessment for advanced immuno-oncology therapy combinations.

Citation Format: Sarah Krueger, Thomas Dailey, Kevin Guley, Maryland Franklin. Image-guided focal irradiation in syngeneic preclinical oncology mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4712. doi:10.1158/1538-7445.AM2017-4712