In the study, investigators dove deep into the biology of metastatic, non-small cell lung cancer to find out what happens on a cellular and molecular level when cancer is treated with a combination of radiotherapy and immunotherapy. Patients received the treatment with or without prior radiation of just one metastasis.
The combination therapy worked better than immunotherapy alone, the investigators describe in Nature Cancer on July 22.
At the core of the research is the idea that radiation could induce a systemic immune response because of a unique phenomenon called the abscopal effect. This is when tumor cells die at the irradiated spots, releasing molecules. Sometimes, the immune system discovers these molecules, learning the tumor’s ‘fingerprint’. This leads to activation of immune cells to attack cancer cells elsewhere in the body, even ones that are far away from the original tumor. Thanks to this effect, radiotherapy could potentially improve the effect of immunotherapy, even in places that haven’t been irradiated.
Willemijn Theelen and Paul Baas from the Netherlands Cancer Institute ran a phase 2 clinical trial in which they investigated the effect of radiotherapy followed by immunotherapy (specifically the PD-1-inhibitor pembrolizumab) in patients with non-small cell lung cancer. The control group received only immunotherapy.
In collaboration with their American colleagues, the team analyzed 293 blood and tumor samples from 72 patients, taken before and during their treatment. The team focused on cold tumors, tumors that typically don’t respond to immunotherapy. These cold tumors can be characterized by particular biomarkers; relatively few mutations, no expression of a protein called PD-L1, or mutations in a signaling pathway called Wnt.
Following radiotherapy and immunotherapy, the team found that cold tumors ‘warm up’. They change from tissue with little to no immune activity, to inflamed sites with strong immune activity, including the expansion of new and pre-existing T cells. Patients with these warmed up tumors showed better clinical outcomes than patients with cold tumors who had been treated with immunotherapy only.
“This research shows that radiotherapy delivered to a small portion of the tumor load can help circumvent certain lung cancer’s insensitivity to immunotherapy,” pulmonologist and researcher Willemijn Theelen says. “This may even work in patients who did respond to immunotherapy at first, but then became resistant. We are currently doing a follow-up study at the NKI looking into this.”
The study was a phase-2 study. In this phase, the researchers test whether a certain type of cancer responds to a new treatment. Does it have the desired effect on the tumors; are cells truly destroyed or is growth halted? A following phase-3 study compares the effect of the new treatment with the current standard. If the new treatment proves effective and safe, it could become the new guideline.