Unleashing the Potential
From Paths of Progress Spring/Summer 2014
by Robert Levy
"It's going to be standing room only. We'd better get there early."
The buzz at some cancer research presentations these days is like the pre-show chatter at a rock concert. But the subject of the excitement isn't the latest pop star, it's research that is unlocking the immune system's power as a cancer fighter. Oncologists who may once have been skeptical about the notion of immune system-based cancer therapies now find themselves enrolling in refresher courses on immunology and doing double-takes at the latest clinical trial results.
Results like these: In 2010, investigators led by F. Stephen Hodi, MD, of Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) reported that a therapy that stifles a key protein on immune system cells extended the lives of patients with advanced metastatic melanoma. In some cases, the gains were extraordinary: About 20 percent of the patients who benefited from the drug are alive today, up to 10 years after treatment. The study marked the first time a drug had been scientifically shown to lengthen survival in patients with the often fatal disease.
Last year brought news of another clinical trial of a drug with a talent for blocking a protein on immune system cells. Investigators at Johns Hopkins University, DF/BWCC, and elsewhere administered the drug to hundreds of patients with cancers that hadn't been tamed by traditional therapies. In all, 18 percent of patients with non-small cell lung cancer had their tumors shrink partially or completely, as did 28 percent of patients with melanoma, and 27 percent of those with kidney cancer. Equally impressive was the length of the remissions: two-thirds of the patients who benefited from the drug were still in remission when investigators checked them a year after treatment.
In a field where survival improvements are often measured in months, findings like these have had an electric effect. The excitement represents a triumph for an approach to cancer treatment called immunotherapy (which mobilizes the immune system to fight disease) that not long ago was the pursuit of a hardy minority of scientists. And it comes as vindication for the handful of research centers – notably Dana-Farber – that incubated the work while other centers took a different tack.
For scientists like Dana-Farber's Gordon Freeman, PhD, whose discoveries about the basic workings of the immune system made many of the new immunotherapies possible, the convergence of research in this area is especially rewarding. "As a basic scientist at Dana-Farber, I often ride the elevator with patients and their families or pass through clinical areas, and it reminds me every day how important our work is," Freeman explains. "It's exciting to know that research I did can really make a difference."
A Scientific Legacy
This new era of cancer immunotherapy is the product of decades of research into the teeming intricacies of the human immune system. The notion that the immune system could be honed into a weapon against cancer is at least 100 years old, but like many attempts to harness a force that's only dimly understood, early efforts were largely unsuccessful.
Real progress awaited discoveries in the 1990s as scientists studied the interaction between immune system T cells and cancer cells. It was known that T cells – the immune system's strike force against foreign invaders and diseased cells – identify cancer cells by latching onto proteins, called antigens, from the cancer cells' surface. The latching is accomplished with specialized proteins called receptors that jut from the T cell surface.
It quickly became clear, however, that T cells do a more thorough job of frisking cancer cells than this simple, one-step procedure would suggest. For along with their receptors, T cells also carry similar structures known as co-receptors. When the co-receptors are stimulated by certain cancer cell proteins, the T cells become active tumor hunters.
Research into T cell receptors and co-receptors suggested a novel strategy against cancer: siphon some of a patient's T cells into a test tube, "introduce" them to some of the patient's own tumor cells, then inject the newly aggressive T cells back into the patient so they can rally the immune system against cancer. This approach to a therapeutic cancer vaccine has been studied and tested by a wide range of researchers, including some at Dana-Farber, but despite showing signs of promise, it has yet to achieve breakthrough success.
"About halfway through the research into co-receptor interactions, there was a surprise," recounts Harvey Cantor, MD, chair of Dana-Farber's Department of Cancer Immunology and AIDS. "We learned that some co-receptors inhibited the immune response, rather than stimulating it."
T cells' response to infection or cancer, it turns out, is more like a deliberation than a reflex. Much as a war council gets input from advocates as well as opponents of military action, T cells receive both "charge!" and "stand down" signals from their co-receptors. Whichever signal predominates determines the T cells' course of action.
Even as discoveries about in-hibitory co-receptors were being published, most research institutions continued to focus on the stimulatory side of the immune response – believing the best approach to an immunotherapy for cancer is one that multiplies both the number and activity of T cells. An exception was Dana-Farber, where research into both aspects of the immune response was afoot.
It wasn't that Dana-Farber researchers had special powers of foresight or were quicker to grasp the potential of therapies that targeted the inhibitory response of T cells, Cantor remarks. It was, rather, the general vitality of immunological research that allowed researchers here to take a broader view. That dynamism was, to a large degree, a legacy of Baruj Benacerraf, MD, the Nobel Prize-winning immunologist who, as president of Dana-Farber from 1980-1992, built the Institute into a mecca for immunology research, Cantor states.
One of the young scientists who came to Dana-Farber during Benacerraf's tenure was Gordon Freeman, PhD, who joined the lab of Lee Nadler, MD, in 1985 as a postdoctoral fellow. With lab-mate Arnold Freedman, MD, he began studying B7, a protein displayed by key immune system cells. Although B7 proteins come in a variety of forms, the ones initially identified issue an activating order to T cells, instructing them to attack.
"We began to look for molecules that were similar or related to B7," Freeman relates. They found several, but it was the discovery of one in particular that helped change the course of cancer immunotherapy.
In 2000, Freeman and his colleagues published a paper announcing the existence of a protein on normal cells called PD-L1 (for programmed cell death 1 ligand 1). Like other members of the B7 family, the researchers wrote, PD-L1 entwines with a T cell co-receptor – in this case, one called PD-1 – deterring the T cell from going into attack mode.
PD-1 and PD-L1 are part of the body's system for self-preservation. They help ensure that T cells – always on the lookout for foreign invaders and diseased cells – recognize normal cells and leave them unharmed. By draping themselves in PD-L1 (and a related protein, PD-L2), cells are essentially hanging a thousand "Do Not Disturb" signs on their membranes.
Freeman's next paper, in 2001, reported a startling finding: PD-L1 appears not only on some normal cells but also on many cancer cells. "Cancer cells have essentially stolen the PD-1/PD-L1 mechanism from normal cells in order to evade attack by the immune system," Freeman says.
The implications of the discovery for cancer treatment were immediately apparent. "Whenever you discover something that inhibits the immune response to cancer, you have a target for a new therapy," Freeman remarks. "We showed that if you block PD-L1 or PD-L2 with a drug molecule, you allow T cells to become more active against cancer cells. T cells start dividing faster – they can be the fastest-dividing cells in the body – and act more aggressively."
Along with the discovery came a new understanding of why tumors usually withstand an immune system attack, and why techniques for juicing up the immune response to cancer have yet to gain more traction. Researchers have found that even though T cells can penetrate deeply within tumors, these T cells are often just milling around in a state scientists call "exhaustion," rather than leading an anti-cancer assault. The reason for this lethargy: The cancer cells within the tumor are blanketed in PD-L1 and sometimes also PD-L2. Therapies that incite the T cells to go on the offensive have the perverse effect of encouraging cancer cells to sprout more of these inhibitors of the immune response. It's as though a legion of horses were saddled and mounted for a cavalry charge, only to have the riders pull ever more tightly on the reins.
Into the Clinic
The publication of Freeman's paper on the immune-inhibiting effect of PD-1 and its protein partners had a liberating effect of its own: Pharmaceutical companies that once balked at pursuing immunotherapies began developing drugs that block PD-1, PD-L1, PD-L2, or some combination of them. Some of those drugs are now being tested in clinical trials, and the initial results, as mentioned above, have been as compelling as any in cancer medicine in recent years. The trial at Johns Hopkins and DF/BWCC may have gotten the most publicity, but others are equally encouraging. (The trial led by Hodi involved a drug that blocks another immune-inhibiting molecule, CTLA-4.) Here are the results of some of these early-stage trials:
An antibody that blocks PD-L1 produced remissions or halted the growth of tumors in many patients with advanced cancers, with improvements lasting more than a year.
A PD-1-blocking antibody sent tumors into a sustained retreat in some patients with advanced melanoma.
A combination of a CTLA-4- blocking agent and a PD-1 blocker produced rapid and extensive tumor shrinkage in a substantial proportion of patients with advanced melanoma.
The hallmark of each of these studies is the staying power of the drugs being tested. While "targeted" therapies – which shut down specific, abnormal genes – often work for a large percentage of patients, the treatments tend to lose effectiveness over time, as cancer cells learn to evade them. Drugs that disinhibit T cells, by contrast, have so far been effective in a smaller proportion of patients, but their benefits are much more durable. Researchers say that combining targeted therapies with the newer T cell-targeting agents may offer the best of both worlds – broad-scale effectiveness and long-lasting benefits.
"The future really is now," Freeman comments. "The challenge is to find the right mix of therapies that create a PD-1 blockade and hit a second target, preferably one with a different mechanism of action. The ability to target cancer cells directly and indirectly, with agents that remove T cell inhibition, is especially promising." If current studies bear fruit, patients will benefit from that promise for years to come.
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