This is a story about the velocity of an idea – a discovery whose potential to improve cancer treatment practically leapt from the test tube. It is a story of the science behind the discovery of PD-1 and immunotherapy.
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 harrassment 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. Today, a half dozen years later, roughly a dozen trials of PD-L1 blockers have been completed and about 50 more are 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 PD-L1 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 early returns from clinical trials at other institutions, checkpoint inhibitors have also shown good results in stomach cancer, 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 anti-cancer arsenal.