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.
The groundwork was laid in the 1990s, when scientists learned that immune cells carry certain proteins on their surface that enable them to turn off the body’s immune system. That was followed by the discovery by Dana-Farber immunologist Gordon Freeman, PhD, and colleagues that many cancer cells wear one of those same proteins, called PD-L1, as 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 2006 in patients with a variety of tumors including melanoma, kidney, and lung. Today, six PD-1/L1 “checkpoint inhibitor” immunotherapy drugs have been approved by the U.S. Food and Drug Administration for 14 different types of cancer, and PD-1/L1 inhibitors are being evaluated in more than 2,250 clinical trials. These trials involve thousands of patients with a wide range of cancer types, including rare cancers.
“It makes sense to test these agents in every form of cancer,” says Freeman, 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. The PD-1 “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 pass by, leaving the tumor cells free to go about their 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 — let the immune system directly kill it.”
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.
The record of clinical research in PD-1/PD-L1 inhibitors is shorter than that of CTLA-4 inhibitors and, in many respects, its durability is just beginning to be written. In addition to the 14 tumor types where PD-1/PD-L1 inhibitors have been approved, in early returns from clinical trials at DFCI and other institutions, checkpoint inhibitors have also shown promising results in mesothelioma, stomach cancer, and some ovarian cancers, with less effectiveness in prostate, pancreatic, or 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 — including 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 is even evidence that radiation therapy works better when joined to treatment with checkpoint inhibitors.