A new study in mice shows that delivering different doses of radiation to a tumor revs up the immune system and allows it to detect not only the treated tumor but distant tumors that were not irradiated. When mixed dose radiation is followed with immunotherapy drugs called immune checkpoint inhibitors, it makes the drugs more effective at killing cancer cells throughout the body than when radiation was delivered at a single dose level.
The study performed by researchers at the University of Wisconsin Carbone Cancer Center used mouse models of melanoma and prostate cancer to further refine the use of radiation therapy. The goal of the researchers is to help the immune system and immunotherapy drugs detect and kill cancer cells, similar to how vaccines prime the immune system to fight pathogens that cause infectious disease.
The study was led by Justin Jagodinsky when he was an MD-PhD candidate in the lab of Dr. Zachary Morris, professor and chair of human oncology, University of Wisconsin School of Medicine and Public Health. It was published in the journal Science Translational Medicine.
The team used brachytherapy, a targeted approach that inserts a radioactive source into a tumor using a catheter. This delivers a gradient of radiation from high dose near the catheter to low dose at regions of the tumor that are most distant from the catheter.
The study shows that each dose leads to a unique immune response: the high dose kills cancer cells in the immediate region of the tumor, the medium dose promotes an immune process called a type I interferon response that plays an essential role in activities like fighting against viruses, and the low dose promotes inflammatory signaling and changes in nearby blood vessels to enable greater trafficking of immune cells into the tumor.
Researchers also found that each dose of radiation causes unique changes in gene expression and the susceptibility of the cancer to immunotherapy drugs. The mixed dose treatment was most effective at boosting tumor-specific T-cells, a type of immune cell that can find cancer cells elsewhere in the body and attack them.
“We found that tumors treated with the heterogeneous dose had much more robust immune activation, with multiple genes and immune pathways upregulated, compared with treating the tumors with a single level of radiation dose,” said Jagodinsky, who is now pursuing radiation oncology residency training at Stanford University. “We saw a strong anti-tumor response to the heterogeneous dose that was much more than additive and that led to a T-cell response at distant tumors that is consistent with in situ vaccination.”
Morris and members of his department use radiation to treat patients with nearly any type of cancer at UW Health | Carbone Cancer Center. He said the study’s encouraging results point to new approaches to optimally using radiation to treat patients whose cancers have stopped responding to immunotherapy drugs. Cancers of the skin, prostate, endometrium, breast, head and neck, or cervix may be the most likely initial targets since those cancers are already treated with brachytherapy.
“The next step could be to see if giving different doses of radiation delivered via brachytherapy can make the tumors more visible to the immune system and improve the response to immune checkpoint inhibitor drugs,” Morris said. “We need to better understand dose selection and timing for the optimal combination of radiotherapy and immunotherapy.”
Other UW School of Medicine and Public Health members of the research team include Jessica M. Vera, Wonjong Jin, Amanda Shea, Paul Clark, Raghava Sriramaneni, Thomas Havighurst, Ishan Chakravarthy, Raad Allawi, KyungMann Kim, Paul Harari, Paul Sondel, Michael Newton, Jessica Miller and Irene Ong.
The work was funded by National Institutes of Health grants P30 CA014520, P50 DE026787, 1DP5OD024576, P01 CA250972, T32 GM140935, TL1 TR002375, F30 CA250263, R35 CA197078 and R01GM102756.