From Paths of Progress Spring/Summer 2015
by Robert Levy
This is a story about the velocity of an idea — a discovery whose potential to improve cancer treatment practically leapt from the test tube.
The groundwork was laid in the 1990s, when scientists learned that human cells carry certain proteins on their surface that enable them to escape attack from the body's immune system. That was followed by the discovery by Dana-Farber scientists that many
cancer cells wear one of those same proteins, called PD-L1 — part of an elaborate masquerade that allows the cancer cells to live and multiply without harassment from the immune system.
The implications of that finding, published in 2001, were self-evident: find
a way to block PD-L1, or the proteins on immune system cells that "see" PD-L1, and the command that once prevented an immune system attack on cancer would be lifted. Pharmaceutical companies, once skittish about investing in immunotherapies for cancer
(agents that sic the immune system on tumor cells), began working on them in earnest.
The first clinical trial of a PD-L1-blocking drug began in 2008 in patients with advanced blood cancers. By the end of 2014, roughly a dozen trials of PD-L1 blockers had been completed and about 50 more were under way at more than two dozen medical centers
across the country, involving thousands of patients with a range of different types of cancers.
These statistics say much about the promise of this form of immunotherapy. First, they indicate that a substantial number of participants in these trials have benefited from it. (New trials wouldn't be opening at this pace if the treatment wasn't already
showing significant signs of success.) Second, they suggest that, unlike some other drug agents, PD-L1 blockers can be effective against multiple types of cancer.
"It makes sense to test these agents in every form of cancer," says Dana-Farber's
Gordon Freeman, PhD, whose lab discovered that PD-L1 resides on normal cells as well as some cancer cells, and that blocking it can provoke an immune system attack on tumors.
This particular type of therapy goes by the name immune checkpoint blockade. "Checkpoint" refers to the encounter between immune system T cells — which patrol the body relentlessly for signs of infection or other disease — and the PD-L1 protein on tumor
cells. T cells use a protein on their own surface, called PD-1, to probe cancer cells for PD-L1 (and a closely related protein, PD-L2).
When they find it, they courteously pass by, leaving the tumor cells free to go about their cancerous business. But when a drug agent blocks that signal, the T cells, no longer misled by PDL1 and PD-L2, rally an immune system attack on the cancer. "This
is a really different strategy," says Freeman. "Don't poison the cancer cell but let the immune system directly kill it."
The early rounds of clinical testing of PD-1/PD-L1 checkpoint inhibitors suggest the arrival of a major addition to the anti-cancer arsenal. The inhibitors, which are made from natural human antibodies, work better in some types of cancers than others,
but a distinctive pattern has emerged from the trials conducted so far: For patients who do benefit from these agents, the benefits tend to last for years — in some cases, it appears, indefinitely.
One of the most dramatic examples comes from a clinical trial led by
F. Stephen Hodi, MD, director of the
Melanoma Center at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). "Since the year 2000, more than 2,000 patients with metastatic melanoma have been treated with ipilimumab, a drug that blocks an
immune checkpoint known as CTLA-4," Freeman relates. "About 20 percent benefited from the drug. The vast majority of them are alive today."
The record of clinical research in PD-1/PD-L1 inhibitors is much briefer than that of CTLA-4 inhibitors and is, in many respects, just beginning to be written. But many of the results are of the sort that led Science magazine to dub this form
of immunotherapy the "Breakthrough of the Year" for 2013.
In a phase 1 clinical trial led by Dana-Farber's
Phillippe Armand, MD, PhD, and
Margaret Shipp, MD,
investigators tested the PD-1 blocker nivolumab in 23 patients with Hodgkin lymphoma (HL) who had exhausted numerous other treatment
options, often including stem cell transplant.
Within two to six months, 87 percent of participants experienced a full or partial remission of the disease. The majority of them were still doing well a year after treatment, when the results were published in the New England Journal of Medicine.
"HL was a particularly attractive target for PD-1 blockade," Shipp says. "The tumor cells often carry a genetic abnormality that causes them to produce large amounts of PD-L1, and the tumor tissue teems with ineffective immune system cells. Blocking PD-1
is a way to restore their effectiveness." The study findings prompted the U.S. Food and Drug Administration (FDA) to designate nivolumab a "breakthrough therapy" for relapsed HL, and a multinational phase 2 trial is now under way.
When researchers tested immune checkpoint inhibitors in mice with
glioblastoma — an incurable form of brain cancer — the results were hardly ambiguous. Half of the mice that received a PD-1 antibody were long-term survivors: after 50 days, they showed no evidence of tumor in their brain.
In mice that received antibodies against PD-L1 and CTLA-4, 25-30 percent were considered cured, says
David Reardon, MD, who led the experiments with Prafulla Gokhale, PhD, Sarah Klein,
Scott Rodig, MD, PhD,
Keith Ligon, MD, PhD,
Shakti Ramkissoon, MD, PhD, and Gordon Freeman. These and other results led to the recent opening of three clinical trials (two led by Reardon) of these agents in human patients.
DF/BWCC investigators opened their first clinical trial of a PD-1 and PD-L1 blocker for patients with
kidney cancer five years ago. About 20-25 percent of the trial participants, many with tumors that defied previous treatments, responded to the checkpoint inhibitor, says study leader
Toni Choueiri, MD, clinical director of the
Lank Center for Genitourinary Oncology. With colleagues
Sabina Signoretti, MD,
Eli Van Allen, MD, and others in the Harvard research community, he is analyzing preserved and fresh tumor tissue for biological signs that indicate which patients are likely to respond best to treatment.
"Lung cancer is one of the cancer types where PD-1 blockers appear to be effective" — a surprise because previous immunotherapy approaches to the disease weren't successful — says
Peter Hammerman, MD, PhD. He and his associates are studying the genetics of
lung cancer to see if certain mutations render tumors more susceptible to immune checkpoint inhibitors.
David Barbie, MD, is studying whether variations in the immune system from one person to another affect its cancer-fighting ability. The researchers also are exploring whether as-yet undiscovered checkpoint
proteins play a role in holding off an immune system attack and could be new targets for immunotherapy.
For some of the
bladder cancer patients treated with a PD-L1 inhibitor in a recent phase 1 trial, the good news couldn't have come faster. At the first evaluation, six weeks after treatment began, there were already signs that
the cancer was responding to it. After 12 weeks, there was tumor shrinkage in 52 percent of the patients whose infiltrating immune system cells had high levels of PD-L1 prior to treatment.
Although more than half of participants experienced adverse side effects to the drug, known as MPDL3280A, none of them were particularly severe, says
Joaquim Bellmunt, MD, PhD, who helped lead the trial. The drug has been designated a breakthrough therapy for bladder cancer by the FDA.
In early returns from clinical trials at other institutions, checkpoint inhibitors have shown good results in
head and neck cancers caused by the HPV virus, and some
ovarian cancers, with less effectiveness in
prostate cancer and
colon cancer, Freeman notes. Much research remains, however, to determine where such agents are likely to have the biggest impact.
The future of immune checkpoint blockers for cancer almost certainly involves combination with other types of treatment — radiation therapy, targeted agents, cancer vaccines, and some chemotherapy agents — Freeman says. A recent study by Dana-Farber's
F. Stephen Hodi, for example, found that
patients with metastatic melanoma who were treated with ipilimumab survived 50 percent longer, on average, if they
simultaneously received an immune system stimulating agent.
There's even evidence that radiation therapy works better when joined to treatment with checkpoint inhibitors. More than a century after scientists recognized the immune system's potential as a cancer warrior, immunotherapy is rapidly becoming a mainstay
of the anticancer arsenal.
Meeting Patient Drives Home the Impact of Research
Radiation and chemo had done little to slow Barry Nelson's lung cancer when he started a clinical trial of an immune checkpoint inhibitor. But within a month, the disease was in retreat, with CT scans showing dramatic shrinkage of the tumors.
Nelson had been initially told he had only two years to live. Now, he was feeling so well, he started bicycling to his medical appointments. Dana-Farber nurse Joan Lucca, RN, MSN, asked if he'd like to meet the man who saved his life. A short
time later, a gentle-mannered man walked up and introduced himself. It was Gordon Freeman, PhD, a scientist of nearly 30 years who leads the team whose discoveries led to the development of Nelson's treatment.
For a laboratory scientist such as Freeman, the opportunity to meet a patient who directly benefited from his work is exceedingly rare. Freeman had as many questions as Nelson did. "I asked him how it felt to get this new drug and when did he know that
it was working?" Freeman says. "He's a real searcher; when the initial treatments failed, he wouldn't take no for an answer."
Nelson was struck by his easy rapport with Freeman. "He said it's marvelous to see that I'm doing so well, getting my health and my life back," Nelson says. "When my doctor showed him scans of how the tumors had shrunk, he wasn't just seeing a report,
but a patient who had these results. It's been great to get to know the person who's given me this gift."
Paths of Progress Spring/Summer 2015 Table of Contents