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Amanda J. Walker, MD
The Johns Hopkins University
RSNA Research Resident Grant
(2013 - 2014)
Investigation of PD-1 Blockade and Hypofractionated Radiation in Lung Cancer to Enhance the Abscopal Effect
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Abstract:
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New and innovative treatment strategies are needed to improve overall survival in lung cancer. Among the most promising novel treatment approaches is cancer immunotherapy, whereby the host immune system is activated to identify and destroy cancer cells. The activation of programmed death-1 (PD-1), a surface receptor expressed on T cells, has been suggested to play a pivotal role in the immune evasion of tumors from host immune system. Blockade of PD-1 with anti-PD1 antibodies has shown promising results in early clinical trials. Hypofractionated radiation (HypoRT) similarly has been shown to promote a pro-inflammatory tumor microenvironement and increases antigen-presentation. A known clinical phenomenon that ties together these two previously described concepts is the abscopal effect, in which local radiotherapy is associated with tumor regression at sites distant from the irradiated site likely via an immunologic mechanism. I hypothesize that anti-PD-1 treatment in combination with hypoRT will improve local response in an autochthonous transgenic lung cancer model and that tumors in the un-irradiated hemi-thorax will also demonstrate improved response rates compared with either modality alone, consistent with the abscopal effect. In addition, I hypothesize that there will be an increase in cytotoxic T cells and decrease in regulatory T cells in the non-irradiated tumors, providing further proof of concept that PD-1 blockade combined with hypoRT can promote an anti-tumor systemic immune response. I plan to use a clinically relevant lung tumor mouse model (CCSP-rtTA/tet-KrasG12D/tetO-Twist1 or CRT) and also have access to an array of other state-of-the-art autochthonous transgenic lung tumor mouse models. The radiation treatments and serial post-treatment assessments will be performed with the Small Animal Radiation Research Platform (SARRP), which allows our lab to test novel pre-clinical radiation-based therapies under conditions that closely mimic those in the radiation oncology clinic.
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