When waiting helps: Arguments for delayed radiation therapy

Just over half of all cancer patients receive radiation therapy at some point during their treatment. The goal is to kill tumor cells using high-energy radiation. As early as the 1950s, a scientist described that molecules released from dying cancer cells into the tumor environment can stimulate the body’s immune system. He observed that, in some patients, radiation therapy worked much like a vaccination against their cancer. Unfortunately, such cases are very rare. As a result, interest in this observation remained low for a long time.

Immunostimulatory effect of radiation

That changed 14 years ago, when the first immunotherapeutic drugs—immune checkpoint inhibitors—made their way into clinical practice. The effect of these drugs is often described as “releasing the handbrake.” They block a contact site on immune cells where cancer cells would otherwise attach in order to signal to the immune cells that they should remain inactive. When this contact site is blocked, cancer cells can no longer exert this influence, and the immune cells attack them. Scientists assumed that with these new drugs it should be possible to make the immunostimulatory effect of radiation therapy apparent more often, that is, in a larger number of patients.

The problem of simultaneous irradiation

Indeed, numerous laboratory experiments produced “not only encouraging results, but also convincing mechanistic explanations for how the combined treatment works,” says Martin Pruschy, head of the Radiobiology Research Group at Zurich University Hospital. However, he adds, “So far, it has only been partially successful to translate the promising early research findings into clinical practice.” In a project funded by the Swiss Cancer Research foundation, Pruschy and his team have now found a possible explanation.

Today, nearby lymph nodes that may be affected by tumor cells are irradiated together with the tumor. “That sounds sensible,” says Pruschy, “but it also poses a problem.” Lymph nodes are central hubs of the immune system. It is in these structures that immune cells exchange information so that some of them can mature into activated defense cells. If the lymph nodes are destroyed before they can process the signals from dying cancer cells, the immune system is, in a sense, deprived of the opportunity to learn from the radiation therapy. “The vaccination effect of radiation therapy is lost,” says Pruschy.

Over several years, his team developed a platform for image-guided irradiation of mice. “With it, we can irradiate individual lymph nodes very precisely—or deliberately spare them,” says Pruschy. In their experiments, the combined effect of immune checkpoint inhibitors and radiation restricted to the tumor led to tumor disappearance in seven out of nine mice. By comparison, in the other groups—those that either received only immune checkpoint inhibitors or a combined treatment that also irradiated the lymph nodes—not a single tumor disappeared.

Allowing time to develop an immune response

In conversation, Pruschy makes it clear that in clinical practice, lymph node irradiation should by no means be omitted. After all, metastases sometimes lodge precisely in these nodes. But what if the lymph nodes were irradiated only a few days after the tumor itself? Would the immune system then have enough time to respond to the signals generated by tumor irradiation? In experiments with mice, this approach worked well. When the researchers irradiated the lymph nodes two days after the tumor, the tumor disappeared in five out of 13 mice. After a longer pause of one week, six out of eight mice were cured.

Further investigations by Pruschy’s team revealed that destroying the lymph nodes impairs the navigation of immune cells. Pruschy explains this by describing a maturation cycle that begins when specific immune cells first come into contact with the irradiated tumor. They then must find their way—carrying signals from the dying cancer cells—to nearby lymph nodes, where they interact with other immune cells. These then mature into activated defense cells, multiply, and spread throughout the body to specifically combat cancer cells.

Technically easy to implement

Intact lymph nodes constantly secrete molecules that become less frequent with increasing distance from the node. The concentration of these molecules serves as a guidance system that immune cells simply need to follow. Irradiated lymph nodes, however, are no longer able to secrete these guiding molecules. As a result, immune cells lose their sense of direction. They no longer know where to carry the signals they have picked up from the irradiated tumor. The results of Pruschy’s team suggest that irradiation of the lymph nodes should be delayed so that the immune system can complete the maturation cycle.

“From a purely technical standpoint, our proposal would be very easy to implement,” says Pruschy. Patients would need to return to the hospital a few days after tumor irradiation to receive subsequent irradiation of the lymph nodes. “That would probably be acceptable,” he believes. For now, however, clinical studies must clarify whether these results can be translated to humans. There is still considerable work to be done before the arguments presented here for delayed radiation therapy can be fulfilled and put into practice.

Project nummer: KFS-5301-02-2021