The notion that the immune system could be honed into a weapon against cancer – the very essence of immunotherapy – dates back at least a hundred years. But driven by discoveries over the last 25 years, immunotherapy is proving itself to be not just a tempting concept, but a potent treatment option for a growing number of cancers.
Researchers laid the groundwork in the 1990s, when they learned that human cells carry certain proteins on their surface that enable them to escape attack from the body’s immune system. Scientists at Dana-Farber Cancer Institute then discovered 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, published by Dana-Farber’s Gordon Freeman, PhD in 2001, were self-evident: find a way to block PD-L1, or the PD-1 protein on immune system T cells that “see” PD-L1, and the command that once prevented an immune system attack on cancer would be lifted.
“This is really a different strategy,” says Freeman. “Instead of poisoning the cancer cell, we are letting the immune system directly kill it.”
By 2008, the first clinical trial of a PD-L1 blocking drug had begun. In 2013, Science magazine dubbed this form of immunotherapy the “Breakthrough of the Year.” And by the end of 2014, about a dozen PD-L1 blocker trials had been completed with about 50 more trials underway.
Today, PD-1 or PD-L1 inhibitors are now Food and Drug Administration (FDA) approved for six cancer types: melanoma, lung, kidney, head and neck, bladder, and Hodgkin lymphoma. An inhibitor targeting the CTLA-4 immune checkpoint, as well as the combination of a PD-1 inhibitor plus CTLA-4 inhibitor is FDA-approved for melanoma. The PD-1, PD-L1, and CTLA-4 inhibitors, alone and in combination with a wide variety of other agents are in clinical trials in over 20 other cancer types.
The inhibitors work better in some types of cancers than others, but a distinctive pattern has emerged: For patients who are helped by these “checkpoint inhibitors”, the benefits tend to last for years – in some cases, it appears, indefinitely.
Today, immunotherapies benefit a relatively small percentage of patients. The challenge is to find out why – and how to bring benefits to others with cancer.
Freeman, one of the pioneers of immunotherapy, says that the future of immune checkpoint blockers for cancer almost certainly involves combination with other types of treatment – radiation therapy, targeted drugs, cancer vaccines, and some chemotherapy agents.
Today, scientists whose work first generated skepticism are now celebrated as visionaries, as the world races to expand the immunotherapy arsenal.