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Small clinical trial finds two forms of immunotherapy may be better than one for treating metastatic melanoma

June 6, 2016
Dr. John Thompson and immunotherapy patient Matthew Flood

Dr. John Thompson and immunotherapy patient Matthew Flood in the clinic at Seattle Cancer Care Alliance, where he received combination therapy that put his advanced melanoma into long-term remission.

Photo by Anne Flood

When Matthew Flood was diagnosed with melanoma in 2005 at 53 years old, his first thought was that he wanted to live to attend the graduations of his two daughters — Erin, from high school; and Jennifer, from college.

Flood’s treatment — surgery to remove the tumor on his thigh and a year of interferon therapy in his hometown of Tacoma, Washington — bought him that much time and more. Shortly after his initial diagnosis, he attended Erin’s high school graduation in a wheelchair.

By the time he finished the interferon therapy in 2006, there was no sign of cancer, and Flood saw Jennifer graduate from college in 2007.

But in 2009, the cancer came back, this time having metastasized and spread to the lymph nodes in his neck.

“It was a complete bolt out of the blue,” said Flood, a former EMT for the Tacoma Fire Department.

That same year, he was able to attend Erin’s college graduation, but it was a difficult time, he said. His Tacoma oncologists had told him he likely had less than a year to live.

Flood chose melanoma specialist Dr. John Thompson at Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center’s clinical care partner organization, for his care. Thompson started Flood on interleukin therapy, an early type of immunotherapy commonly used for advanced melanoma at the time.

It bought him just six months before the cancer came back. 

At that point, they were out of conventional options, Flood said. So Thompson pointed him to a clinical trial led by his colleagues, Fred Hutch immunotherapy researchers Drs. Aude Chapuis, Phil Greenberg and Cassian Yee. (Yee is now at MD Anderson Cancer Center.)

Flood became one of 10 patients with metastatic melanoma treated with an experimental combination of immunotherapies between 2011 and 2013. In a study published today in the Journal of Clinical Oncology, the research team described the small clinical trial and how the patients have fared in the years following their treatment.

Flood is now in complete remission five years after receiving the combo immunotherapy. But not all trial participants responded as well as he did — only one other patient is still in complete remission.

Two patients had a partial response but then their disease eventually progressed during the trial. Both had metastases to the brain; Chapuis said this could mean that the therapeutic T cells aren’t able to cross the blood-brain barrier, although they don’t know for sure. Three other patients progressed, and three had stable disease (their tumors neither grew nor shrank).

The results are promising enough that this combo approach warrants further exploration for treating patients with advanced melanoma or possibly other cancers, said Chapuis, study author and Fred Hutch immunotherapy researcher.

“It really opens the door to more combination trials,” she said.

Promising results to pursue further

And such combinations may be necessary for solid-tumor cancers, said melanoma clinical researcher Yee. Tumors like melanoma exist in a complex physical and molecular environment in the body, meaning building a working immunotherapy for solid tumors is a higher hurdle than for diseases like leukemia and lymphoma.

“There’s no question that combination immunotherapy is important,” Yee said.

The trial tested a combination of T-cell therapy, a treatment approach that enhances or otherwise modifies a patient’s own immune cells to more powerfully recognize and attack tumors, and ipilimumab, a drug known as a “checkpoint inhibitor” that releases the brakes on the body’s natural immune system, also allowing it to better recognize and attack the cancer.

In 2011, when the study began, patients with melanoma that had metastasized, or spread throughout the body, faced an average survival time that could be measured in months, Chapuis said. Today, such patients have more options for treatment, including a combination of ipilimumab and another type of checkpoint inhibitor, a class of drugs that includes Keytruda, the drug former President Jimmy Carter received for melanoma that had metastasized to his brain.

With only 10 patients treated on the trial, the numbers aren’t large enough to definitively compare this group to the average patient with advanced melanoma, Chapuis said. But five of the 10 patients were still alive three to five years after starting the treatment, results Chapuis said are on par with those for patients now treated with the checkpoint inhibitor combination.

“But 10 patients is really not enough, it just gives you the flavor to continue further,” she said.

The combination of T-cell therapy and a single checkpoint inhibitor drug also seems to have fewer side effects than the two inhibitors together, the researchers found. The patients who received ipilimumab with T-cell therapy had no more side effects than are typically seen with ipilimumab alone.

For the study, the researchers also looked at the molecular details of the T cells the patients received. In those patients for whom the therapy worked — those with remissions or stable disease — they found that the T cells persisting in their blood had a type of molecular signature that’s linked with better T-cell survival and cancer-killing activity.

Dr. Aude Chapuis

"It really opens the door to more combination trials," said Fred Hutch's Dr. Aude Chapuis of the initial results of this small immunotherapy trial.

Fred Hutch file

‘A perfect comparison’

All the patients on the trial had received previous treatments for their cancers. But Flood’s case was unique, Chapuis said, because he’d actually received both ipilimumab and an earlier version of T-cell therapy on their own before starting the combination trial, through different experimental trials at SCCA.

Neither of those therapies worked on their own to halt the cancer. That’s not unusual for metastatic melanoma, Chapuis said, especially with the immunotherapies that were available in 2011. Today’s versions of T-cell therapy have several advantages over the 2011 types, including some approaches that involve engineering the cells to more specifically recognize and attack the cancer as well as persist longer in the body. The approach the researchers used in the study is known as endogenous T-cell therapy, or ETC therapy, and involves selecting — and multiplying in the lab — the very small numbers of T cells in a patient’s body that naturally recognize and attack the cancer.

Together, the two treatments drove Flood’s cancer into complete remission. The researchers theorized this was because the checkpoint inhibitor boosted the anti-tumor activity of not only the body’s untouched immune cells, but also of the cells used in the T-cell therapy.

“It’s really a perfect comparison … suggesting that you can probably ‘rescue’ patients who do not respond to one form of treatment by doing combinations,” Chapuis said, although she also mentioned that the second round of T cells Flood received had some technological improvements over his first round.

The researchers described Flood’s treatment in a case study published last week in the Journal of Experimental Medicine.

Chapuis stressed that this particular therapy combination isn’t likely to see the light of the clinic — at least not that exact incarnation, as T-cell therapy has evolved so quickly since 2011 — but she hopes to eventually start trials looking at the combination of ipilimumab or Keytruda with her team’s current T-cell therapies for other types of cancers, including certain leukemias and lymphomas. The Fred Hutch immunotherapy group doesn’t currently have trials open testing engineered T-cell therapy for melanoma, although Chapuis said it’s on their radar.

Yee said his MD Anderson team is pursuing the approach for several solid tumors.

“It’s a recipe we’re hoping to take beyond melanoma,” he said.

For Flood, who said he’d heard talk about the promise of immunotherapy as someone “on the fringes of the medical establishment” as an EMT, the trial and other advances in melanoma treatment have shown him there are more treatment choices now for patients like him. When Flood was first being treated for his metastases, he was only thinking about the weeks ahead and the two-week cycles of his interleukin therapy, which he said was by far the most grueling of any treatments he received.

After finishing the interleukin, he started to think about reaching goals a few months out, he said. And then, when the experimental immunotherapy started working, he allowed himself to think of events that might happen a few years in the future. Now he doesn’t even think about his life in those terms, he said.

“Now even if the cancer came back I’d have some pretty good options,” he said. “You’re not looking at dying within a three-month or six-month period now.”

Rachel Tompa, a staff writer at Fred Hutchinson Cancer Research Center, joined Fred Hutch in 2009 as an editor working with infectious disease researchers and has since written about topics ranging from nanotechnology to global health. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Reach her by email at rtompa@fredhutch.org or follow her on Twitter at @Rachel_Tompa.

For information about participating in a cancer clinical trial, please contact Fred Hutch’s clinical care partner, Seattle Cancer Care Alliance, or send an email to: intake@seattlecca.org. Another good resource about clinical trials is the National Cancer Institute’s Cancer Information Service, which can be reached at 1.800.4.CANCER. The phone line is staffed from 8 a.m. to 8 p.m. ET Monday through Friday.

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