Triple therapy for rare skin cancer shows promise in small, early-stage trial

Combo of T-cell therapy, newly FDA-approved drug and another immune booster kept cancer at bay for three of four patients with metastatic Merkel cell carcinoma
Fred Hutch immunotherapy researcher Dr. Kelly Paulson is seeing promising results in a small, ongoing trial for patients with advanced Merkel cell carcinoma. Photo by Robert Hood / Fred Hutch News Service

Three out of four patients treated with an experimental combination of three different therapies for the rare skin cancer known as Merkel cell carcinoma are in complete remission following the treatment, according to study results from a small clinical trial led at Fred Hutchinson Cancer Research Center. Fred Hutch immunotherapy researcher Dr. Kelly Paulson will present interim results from that study and a previous double-therapy study in a poster on Monday, June 5, at the 2017 annual meeting of the American Society of Clinical Oncology in Chicago.

The trial, which is still ongoing, combines a form of T-cell therapy; a newly FDA-approved immunotherapy drug known as avelumab, which is a checkpoint inhibitor made by EMD Serono; and either radiation or interferon, a general immune system booster that renders the tumors more visible to the immune system. Paulson likens the approach to building a fire.

“We’ve got the tumor and we upregulate [a certain protein using radiation or interferon] to throw some kindling on, and then we put the T cells in to light the match, and then we put the checkpoint blocker in to fan the flames,” she said.

This small study of four patients with advanced Merkel cell carcinoma built off a previous study, also of four patients, that tested a double combination of just T-cell therapy and radiation or interferon. The patients in that study did not fare as well — three of them saw their cancer progress, and two of those patients have since died. Although T-cell therapy, a form of immunotherapy that manipulates or engineers a patient’s own immune cells called T cells to better fight the cancer, is showing promise against some blood cancers, solid tumors like Merkel cell carcinoma seem to be a tougher nut to crack.

In their current study, the addition of avelumab seems to have kicked the T cells into high gear, Paulson said. When the researchers tracked the cells in the patients’ bodies, they saw that the immune cells traveled from the bloodstream, where they are administered, to the tumors. And the cells stayed at the tumor sites for months, even when the tumor was no longer clinically detectable.

All four patients who received this triple therapy saw their cancer shrink in response; three of them are now in what’s known as complete remission, where biopsies of their tumor sites show no evidence of remaining cancer cells. The fourth patient had a partial response — his tumors shrank but did not disappear completely — and his cancer later progressed. The researchers have now followed the patients for a median of 12 months since the start of the trial.

Rose Wittman, 59, was diagnosed with Merkel cell carcinoma in 2015. Her doctors found the cancer had spread while she was still undergoing her initial treatment. Photo courtesy of Rose Wittman

‘Am I imagining this?’

Rose Wittman was the first patient enrolled in the triple-therapy trial. The 59-year-old P.E. teacher and volleyball coach of Salina, Kansas, was first diagnosed with Merkel cell carcinoma in 2015. The cancer was found in her lymph node, meaning it had already spread from her original tumor. Wittman flew to Seattle to see Dr. Paul Nghiem, a University of Washington and Fred Hutch skin cancer researcher who specializes in Merkel cell carcinoma and is also an author on the study presented at ASCO. Wittman was treated at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner, but — like many with this rare cancer — saw her disease return. She was in the middle of radiation treatment when she found a new lump on her neck. A scan confirmed it was the cancer and revealed another tumor in her armpit.

Merkel cell carcinoma metastasizes, or spreads throughout the body, in one-third of patients even with prior treatment, and when it does, it’s often deadly — historical five-year survival rates for patients with metastatic disease are less than 10 percent. All the patients enrolled in the two small Fred Hutch trials had metastatic cancer.

At that point, Wittman said, Nghiem told her a clinical trial was her best option. But even though the lump in her throat was growing, it wasn’t large enough to qualify her for the double-therapy trial open at that time, in the fall of 2015. So Wittman went home to wait for her cancer to grow bigger. By the end of the year, the tumor was large enough, and the triple-therapy trial had just opened.

Getting her T cells extracted didn’t feel any different from a normal blood draw, Wittman said, and she was lucky to not experience any noticeable side effects. Many of the other patients in the trial saw some side effects, Paulson said, although none were dangerous or unexpected. Nearly all the patients in the two studies experienced lymphopenia, or reduced white blood cell counts, and three out of the eight had cytokine release syndrome, a general inflammatory response that T-cell therapy can sometimes trigger. None of the patients had to be admitted to the intensive care unit and the side effects were transient, Paulson said.

Wittman described the tumor in her neck as being about the size and firmness of a golf ball. It got large enough that friends and students at her school started asking her about it while she was waiting to enroll in the trial, she said. When she received the radiation and the subsequent T-cell infusion, she could feel the tumor softening under her fingers, Wittman said.

“Within 24 hours, I said, ‘Am I imagining this?’” she said. “Within a week it was almost all gone, it was just that fast.”

And the scans backed that up — by her second scan in the trial, two months after starting the T-cell therapy, there were no detectable tumors left. Now nearly a year and a half past the start of her experimental treatment, Wittman knows there’s always a possibility her cancer could come back again, but she’s hopeful, she said.

A foundation for other solid tumors

Although the trial of triple therapy is small — only four patients have received the therapy and another two are enrolled to begin treatment soon — Paulson thinks it’s a promising foundation for future T-cell therapy studies. Paulson, who is also an oncology fellow in the laboratory of Fred Hutch immunotherapy researcher Dr. Aude Chapuis, and her colleagues at the Hutch and UW had reason to hope this form of immunotherapy would be safe and effective for patients with this rare skin cancer, which afflicts about 2,000 in the U.S. every year, primarily the elderly.

The majority of Merkel cell carcinomas are caused by a common virus known as the Merkel cell polyomavirus, and most patients who have this cancer have a high level of one of the virus’ proteins present in their tumors — but nowhere else. That situation is an ideal setup for a working T-cell therapy, Paulson said, because therapeutic T cells need to recognize and attack tumor cells but spare healthy cells. T cells that attack both tumor and healthy tissue can lead to toxic side effects. In this case, the viral protein serves as that T-cell target.

For their current study, only patients who already have T cells that react to the viral protein are eligible. About 15 to 25 percent of Merkel cell carcinoma patients make this kind of T cell naturally, Paulson said. The researchers extract those cancer-recognizing T cells from the patients’ blood and multiply them in the lab before reinfusing them.

In the next iteration of the experimental therapy, which the team is now developing in the lab, Paulson and Chapuis hope to engineer T cells to recognize the cancer cells, thereby broadening the therapy’s potential to more patients.

Paulson also hopes the team’s work will lead to insights that can apply beyond just this rare cancer.

“These are a really deserving group of patients and I love working on Merkel cell cancer, but I also know that the most impact is going to be made by spreading what we know about Merkel to other [cancers],” she said.

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Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. 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. Follow her on Twitter @Rachel_Tompa.

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