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• W1991668021 abstract "Blockade of the PD-1/PD-L1 pathway has shown promising clinical results in patients with non-small cell lung cancer (NSCLC). Radiation therapy (RT) has been shown to increase antigen presentation and promote a pro-inflammatory tumor microenvironment, and we have previously shown that PD-1 blockade synergizes with RT in an orthotopic glioma model. We hypothesized that the combination of -PD-L1 antibody and RT would enhance tumor response in a physiologically relevant autochthonous murine model of NSCLC. Given the complimentary roles of CTLA-4 and PD-1 pathways in the adaptive immune response, we also examined the effects of combining -CTLA-4 with -PD-L1 and RT. Transgenic mice with KrasG12D-/Twist1-induced lung adenocarcinoma were stratified into one of six treatment groups: (1) isotype control, (2) -PD-L1, (3) -PD-L1 + -CTLA-4, (4) RT + isotype, (5) RT + -PD-L1, and (6) RT + -PD-L1 + -CTLA-4. Image-guided RT (15 Gy x 1) was delivered to the right hemithorax and tumor response assessed by serial microCT scanning. Mice were sacrificed after treatment to confirm tumor burden and to quantify immune infiltrate in the tumor and draining lymph nodes. Checkpoint blockade alone (-PD-L1 or -PD-L1 + -CTLA-4) decreased the rate of tumor progression compared to isotype control (p < 0.05). Similarly, RT alone led to a decrease in tumor size at week 1 (p = 0.03), but animals showed evidence of progression by week 3. The only animals demonstrating either complete or durable responses at week 3 and beyond were treated with both checkpoint blockade and RT. Both antibodies + RT led to an average 60% decrease in tumor size at week 3 (p < 0.01) and 80% decrease in tumor size at week 6 (p = 0.01). There was also decreased tumor growth in the contralateral unirradiated hemithorax in mice treated with checkpoint blockade and RT providing some evidence for an abscopal effect (p = 0.01). Posttreatment, we found an increase in CD8 effector cells (CD8+/IFN+) in the lungs of treated mice, and did not find an increase in regulatory T cells (CD4+/Foxp3+) or activated CD4 T cells (CD4+/IFN+). This increase in cytotoxic T cells was seen in both the irradiated and unirradiated lungs with the greatest change after treatment with combined RT plus -PD-L1 and -CTLA4 antibodies (p < 0.05). The combination of checkpoint blockade and RT in an autochthonous model of NSCLC significantly improved local tumor response in the irradiated lung with partial tumor response in the unirradiated lung. An increase in cytotoxic T cells was observed in both irradiated and unirradiated lungs after radiation and checkpoint blockade. This preclinical study provides evidence to support combination trials with RT and checkpoint blockade." @default.
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• W1991668021 date "2014-09-01" @default.
• W1991668021 modified "2023-10-16" @default.
• W1991668021 title "Combining Checkpoint Blockade With Radiation Therapy Results in Tumor and Immunological Responses in an Autochthonous Mouse Model of Lung Cancer" @default.
• W1991668021 doi "https://doi.org/10.1016/j.ijrobp.2014.05.199" @default.
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