Catherine Spina: Where Radiation Meets Immunology

Miracles sometimes happen in cancer treatment and Catherine Spina is a witness.

“Abscopal response” is the term often used by radiation oncologists like Spina to describe such patients, whose metastases vanish after a single tumor has been irradiated.

The abscopal response (ab scopus means away from the target in Latin) was first described in mice in the 1950s. Oncologists were initially skeptical that anything like this could happen in people, and it took two decades before a human case was documented. As more cases were reported, the oncology field began to investigate the underlying mechanisms. Cases are still exceedingly rare; probably fewer than 100 have been reported in the literature. Researchers have learned that the immune system is required, in this setting, to shrink tumors distant from the irradiated tumor. This has caused great excitement as the clinical and scientific communities wondered if they could intentionally trigger an abscopal effect in patients routinely.

Spina, now assistant professor of radiation oncology, was a resident at Columbia when she first encountered her abscopal patient (although no one knew at the time that his cancer was destined to vanish). He had been diagnosed with cancer years earlier and was treated with brachytherapy, radioactive seeds implanted in the prostate. But 13 years later, the disease had returned. He marched through the standard hormonal therapies, moving onto less therapeutically certain clinical trials. Given his limited therapeutic options, his prognosis at the time was poor.

Spina herself was progressing through her residency program. She left the patient’s care team, and her focus turned to research.

In the lab, Spina started looking for ways to use radiation to enhance the immune response against cancer.

“We often talk about radiation as if it's one thing—let’s treat the patient with radiation,” says Spina. “But it’s more like a pharmacy of drugs, because we offer different doses and schedules of treatment delivery that cause different biological effects. You can adjust the dose and treatment schedule of radiation to achieve different clinical responses and outcomes.

“Inside individual cells, it’s even more complex. We are still trying to understand the best ways to use radiation to stimulate a productive immune response.”

Understanding how radiation changes the immune system

When researchers first investigated how radiation can rouse the immune system to attack cancer, they focused on the T cells that directly kill the cancer cells. Spina takes a wider view to look at the response by other immune cells.

“We now have the tools to look at how all parts of the immune system respond to radiation simultaneously. If you zoom in to look at only one cell type, you may very well miss important changes to another type of immune cell.”

Spina’s work has revealed that radiation activates immune cells distinct from T cells that are critical to the immune system’s response to cancer.

These cells, called myeloid cells, react to radiation in a completely different manner compared to cancer-killing T cells: The radiation-activated myeloid cells are suppressive and blunt the anti-cancer response.

Research and clinic converge

At this point, about five years ago, Spina’s patient and her research unexpectedly converged.

In the lab, Spina found that the irradiated myeloid cells use adenosine, a known immune suppressant, to subdue the immune system’s assault on cancer. Cancers contain a lot of adenosine (even before irradiation) compared to healthy tissue. Around this time, pharma companies were starting to test adenosine blockers in patients.

The Columbia patient was enrolled on one of these adenosine blocker trials but had to pause treatment when he broke his leg. The fracture was the result of cancer that spread into and destabilized his bone. A metal rod was inserted into the diseased bone for stabilization. Afterward, his repaired bone was irradiated by Spina to reduce the odds that the cancer would continue to grow and cause another fracture.

Spina had not been involved with his care for several years but heard about his progress later during a chat with his oncologist.

“I fell off my chair when I heard,” Spina says. “These cases are so rare, I didn’t believe it at first.”

Just weeks after the patient completed radiotherapy and returned to the adenosine blocker trial, his PSA plummeted from 180 (it’s usually around 4 when no prostate cancer exists) to zero.

“I couldn’t believe it! The untreated metastases in his bones and chest just disappeared,” Spina says. “He experienced a real abscopal response—and his PSA has been undetectable for almost five years now.”

The patient’s remarkable response suggested that adenosine blockers—combined with radiation—can ignite the immune system to induce a clinically meaningful cancer response throughout the body.

“It's just one patient, but it means it’s possible. We stumbled upon adenosine signaling pathway in the lab at the same time. I was struck that this is likely a real signal worth pursuing. This is the moment when we began to think that this idea of combining radiation and targeted adenosine drugs had immense potential.”

Lab findings lead to new clinical trial

Spina started working with animal models, testing the combination of adenosine blockers with radiation and checkpoint inhibitors.

Adenosine blockers alone didn’t seem to work. The trial that enrolled the Columbia patient failed, and the pharma company that made the drug closed its adenosine program.

“We found that by adding radiation to the combination of adenosine inhibitors and immune checkpoint blockade, we’re able to cure tumors in mice,” Spina says.

Spina is now testing the idea in a clinical trial—which just opened for enrollment in August—for patients with metastatic prostate cancer. Patients will receive radiation directed at their metastases, two different experimental drugs to block the adenosine pathway, and a checkpoint inhibitor to help boost the immune system.

There’s a lot of excitement about the trial among radiation researchers. Spina was invited to present her research to NRG Oncology, a group that selects promising ideas to test in large multicenter trials. And she’s also working with other pharma companies to see if their adenosine blockers and radiation can improve outcomes for patients with lung cancer.

“If my crystal ball is accurate, I think this is a general, biological phenomenon that’s not specific to one type of cancer. If this is true, it’s a really exciting discovery as a researcher and a radiation oncologist,” Spina says. “To create a drug that will improve responses to radiotherapy across the board, that would be amazing, right?”