Combining low-dose radiotherapy with immunotherapy eradicates metastatic cancer in mice

More doesn’t necessarily mean better — including in cancer treatment.

University of Wisconsin–Madison and University of Pittsburgh School of Medicine scientists report today in the journal Science Translational Medicine that combining targeted radiopharmaceutical therapy with immunotherapy significantly boosts eradication of metastatic cancer in mice, even when the radiation is given in doses too low to destroy the cancer outright.

“We’re excited — with such low doses of radiation, we didn’t expect the response to be so positive,” says lead author Ravi Patel, assistant professor at Pitt and radiation oncologist at UPMC Hillman Cancer Center. “In clinical trials, we tend to go with the maximum tolerable dose, the idea being that radiation kills the cancer and the more we give, the better. But in this study our concept is different — we’re not trying to destroy the tumor with radiation, we’re trying to trigger the immune system to kill the cancer.”

Immunotherapy has revolutionized cancer treatment by helping patients’ immune systems fight off cancer. But some patients develop resistance to current immunotherapies and others have cancers characterized by immunologically “cold” tumors, which evade or suppress the patient’s immune response against his or her cancer.

In these cases, oncologists have found that external beam radiotherapy, or EBRT — where a patient is placed in a carefully calibrated machine that aims a beam of radiation directly at their tumor — can help turn “cold” or resistant tumors into “hot” tumors against which the immunotherapy treatments work better.

But EBRT cannot typically be delivered to all tumor sites in patients whose cancer has metastasized, or spread to other parts of their body, because distant tumors can be too small, plentiful and diffuse for the patient to tolerate so much radiation. In those cases, targeted radionuclide therapy can be an option. This treatment approach uses a radioactive element that is linked with a cancer-targeting molecule and given through an intravenous infusion, delivering radiation directly to the cancer cells upon decay of the radioactive element.

Patel, senior author Zachary Morris, a professor of human oncology in the University of Wisconsin School of Medicine and Public Health, and their colleagues designed a study to give mice with immunologically cold metastatic cancers varying doses of targeted radionuclide therapy alongside immunotherapy.

“Because radiation from a targeted radionuclide therapy, if given at too high of a dose or at the wrong time, could kill or damage the tumor-infiltrating immune cells that we ultimately want to destroy these tumors, it was critical to design these studies with a precise understanding of the radiotherapy dose and the time over which this would be emitted in the tumor,” Morris says.

To accomplish this precision, Patel and Morris worked closely with a team of medical physicists led by Bryan Bednarz, a professor of medical physics at UW–Madison. By obtaining serial images of the radiation emitted by a targeted radionuclide therapy, this group was able to determine how much and when radiation would be delivered to a tumor and to other healthy tissues.

To the researchers’ surprise, the mice given both immunotherapy and doses of targeted radionuclide therapy that were much too low to kill the cancer when given alone were the ones that were cured.

Instead of destroying the tumors, Patel says, the low-dose radiation was “stressing cells in the tumor,” stimulating the tumor cells to activate a type of response that is more commonly seen in settings where cells have been infected by viruses. Boosted by the immunotherapy, the immune cells attacked the cancer cells that had been damaged by targeted radionuclide therapy.

Additionally, when tumor cells were reintroduced to the mice cured by the combination therapy, they quickly fought them off and did not develop cancer again.

“Treating with low-dose radiotherapy and immunotherapy not only eradicated their cancer, it acted as a sort of anti-cancer vaccine, preventing the mice from getting this type of cancer again,” says Patel, who performed the research at UW–Madison as a Bentson Translational Research Fellow.

In addition to the mouse studies, the physician-scientists worked together with David Vail at the UW–Madison School of Veterinary Medicine and tried the combination of targeted radionuclide therapy and immunotherapy as a treatment in pet dogs who had naturally occurring metastatic cancer. The dogs tolerated this treatment combination well, without toxic side effects.

The researchers are continuing to monitor the dogs treated in this study to evaluate how well the combination therapy works as a cancer treatment in this veterinary setting, which closely mimics the diversity of patients and tumors that would be encountered in clinical settings with human cancer patients.

In both animal studies, the researchers used a new targeting agent that can target nearly any type of cancer at any location within the body. This agent was developed by SMPH professor of radiology Jamey Weichert in collaboration with Reinier Hernandez, UW–Madison professor of medical physics. A Madison-based start-up company, Archeus Technologies, is now completing studies needed to apply for approval from the Food and Drug Administration to begin testing this agent in human clinical trials.

“Human clinical trials are needed in order to develop our finding into a new standard of care,” says Patel. “In the meantime, the concept of this approach can be tested in humans now, using approved radiotherapies designed to target specific types of cancer.”

This research was supported by National Institutes of Health grants K08CA241319-01, 1DP5OD024576-01, U01CA233102, R35CA197078, U54CA232568, TL1TR002375, F30CA250263, T32CA009206, P01CA250972, U54 HD090256 and T32 GM008692.

A version of this story originally appeared on the University of Pittsburgh School of Medicine website.