When Roslyn Meyer first noticed a hard pea-sized lump below her left ear in August 2005, she didn’t think much of it. The then-56-year-old mother of three was active, rode her bike regularly, and was generally feeling fine. “It never even crossed my mind that it was cancer,” says Meyer, a clinical psychologist at Yale University in New Haven, Conn. However, almost two months later, doctors determined she had stage IV melanoma. Over the next few years, Meyer received a variety of treatments and surgeries, each with varying degrees of success.
By the summer of 2008, the cancer had spread to the point where dozens of tumors filled her abdomen. As part of a clinical trial at the National Cancer Institute (NCI) in Bethesda, Md., she was treated there with an experimental cancer immunotherapy, a type of treatment that harnesses the body’s immune system to fight cancer. Meyer’s particular protocol involved removing T cells, a kind of immune cell that helps seek out and destroy foreign cells and pathogens in the body, growing billions of these cells in a lab, and then infusing them back into her body to fight the cancer.
Meyer recalls feeling nervous about the treatment because the particular form of immunotherapy she was about to receive had never before been tested in humans. “But I also understood that I was dead if I didn’t have it,” she says. Of the more than 76,000 people who were diagnosed with melanoma in the United States in 2013, about 4 percent were diagnosed with metastatic melanoma. About 15 to 20 percent of these patients will survive more than five years. For Meyer, the therapy and its side effects were intense, and she remained in the hospital in Bethesda for nearly a month. But in March 2009, the pathology report from one final surgery revealed no more signs of cancer.
Meyer’s recovery from stage IV melanoma is part of a larger story taking shape in oncology, as cancer immunotherapies increasingly are attracting attention from both academic researchers and drug companies. Encouraging results from recent clinical trials are drawing more researchers to the field, and a number of new cancer immunotherapies may be nearing approval by the U.S. Food and Drug Administration (FDA). Though many cancer immunotherapies to date have focused on melanoma, researchers are discovering that immunotherapies can be used to treat a whole host of common cancers, including blood cancers and solid tumors.
This is positive news not only for patients with advanced cancers who until recently have had few options, but also for researchers who have been struggling to show the world that cancer immunotherapies work—and not just for a few patients, but for a significant number of them. People have been interested in harnessing the immune system to fight cancer for more than a century, yet the research proceeded in fits and starts. During the mid-1980s, researchers demonstrated that a therapy called interleukin-2 could work, but not as easily or in as many people as had been hoped, says Jedd Wolchok, a medical oncologist and immunologist at Memorial Sloan Kettering Cancer Center in New York City. Some researchers were skeptical of the budding research area, and many doctors continued to focus on standard cancer treatments: surgery, radiation and chemotherapy. But a better understanding of the complexities of the immune system eventually led to more precise and sophisticated immune therapies, more and more of which are showing promise today. “We spent an awful lot of time, several decades, concentrating on how to treat the cancer,” says Wolchok. “Now [with the new immune therapies] we’re in a position to treat the patient.”
Raising an Army
Therapies that rely in some way on components of the immune system have been available for some time. Bone marrow transplantation—replacing diseased or damaged bone marrow with healthy bone marrow stem cells—and the use of antibodies that target cancer cells by binding to specific proteins found on the surface of tumor cells and stopping the cells from growing—like Herceptin (trastuzumab), which binds to the protein HER2—are in many ways different forms of immunotherapy. “But the idea of getting somebody’s own immune system to be able to recognize and destroy tumor cells has been much more challenging,” says medical oncologist Glenn Dranoff at the Dana-Farber Cancer Institute in Boston.
For more than two decades, cancer immunologist Steven Rosenberg, the chief of surgery at the NCI, has been working on a form of immunotherapy called adoptive immunotherapy—the same treatment received by Meyer, who was his patient. A number of research studies have found that the body naturally produces anti-cancer T cells that will migrate to certain tumor cells, and this response is particularly strong in melanoma. Yet within the tumors of metastatic melanoma patients, these T cells, known as tumor-infiltrating lymphocytes (TILs), are not numerous or effective enough to mount a serious attack.
Seeking a stronger effect, Rosenberg and his colleagues found they could isolate a patient’s TILs, grow them in large numbers in the lab, and infuse them back into the patient along with interleukin-2. What’s more, giving the patient a lymphodepleting regimen—a round of chemotherapy, or chemotherapy plus whole-body radiation—to wipe out the patient’s immune cells prior to treatment allowed the lab-grown TILs to go in and do their job without having to compete with other types of immune cells that might block their action.
In a series of three clinical trials involving 93 patients with advanced melanoma who received Rosenberg’s TIL therapy, 20 patients saw their tumors completely disappear and 19 of those 20 have remained in remission for five or more years. “That’s far in excess of anything one sees with any other treatment,” says Rosenberg.
The potential to achieve a long-lasting complete response in patients with melanoma has encouraged researchers to try adoptive immunotherapy against different cancers. However, TILs, they have found, are either absent or too difficult to isolate in other tumor types. To get around this problem, researchers are finding ways to genetically engineer a patient’s own immune cells before growing them in large numbers and infusing them back into the patient.
Immunologist Carl June and his colleagues at the University of Pennsylvania’s Abramson Cancer Center in Philadelphia, for instance, have engineered T cells that target malignant B cells in two types of leukemia. The researchers use a genetic trick to attach antibody-like proteins called CARs, or chimeric antigen receptors, to a patient’s T cells. These CARs are designed to latch onto a protein called CD19 found on the surface of B cells. Once the genetically modified T cells bind to the B cells, they become activated and destroy the B cells.
In 2011, June and his colleagues reported results from a pilot trial in which they treated three adults with chronic lymphocytic leukemia (CLL). Two of the three patients went into complete remission and are still in remission today. The following year, the same team reported testing the therapy on a 7-year-old girl with acute lymphoblastic leukemia (ALL). She too went into remission and continues to have no signs of the disease. “We now know that [the response] is durable,” says June. “That’s really exciting.”
In December 2013, he and his colleagues presented interim results from clinical trials that are testing their genetically engineered T cells in 32 adults diagnosed with CLL, as well as 22 children and five adults diagnosed with ALL. Among those with ALL, 86 percent of the children and all five adults went into complete remission. About half of the patients with CLL responded to the treatment and seven went into complete remission. (Complete remission does not mean cancer is permanently gone; as of December 2013, at least half a dozen of these patients had relapsed.)
The next big hurdle is figuring out how to use genetic engineering to make adoptive immunotherapy work in solid tumors other than melanoma. For that, researchers are seeking to modify T cells to target proteins found on the cancer cells of various tumor types. June, along with University of Pennsylvania oncologist Gregory Beatty, recently engineered T cells that can bind to a protein called mesothelin found on pancreatic cancer cells and are now testing this therapy in a small pilot study. Several other groups are focusing on a protein identified by researchers at Memorial Sloan Kettering, called NY-ESO-1, which is produced in about one-third of some of the most common cancers, including breast, prostate, lung, ovarian, thyroid and bladder cancer. In a phase II trial launched in the fall of 2013, Rosenberg and his colleagues began treating patients diagnosed with various types of metastatic solid tumors using T cells engineered to target the NY-ESO-1 protein.
Re-educating the immune system to recognize and fight cancer with a therapeutic vaccine has been much more difficult and challenging than with other kinds of immunotherapy. So far, only one therapeutic vaccine has received FDA approval: Provenge (sipuleucel-T) was approved in 2010 for the treatment of men with metastatic prostate cancer.
Part of the reason vaccines have not lived up to their potential is that even though a vaccine might generate an immune response, molecular signals in a patient’s body put the brakes on that response, says medical oncologist Glenn Dranoff of the Dana-Farber Cancer Institute in Boston. Therefore, he and his colleagues are looking at combining cancer vaccines with checkpoint inhibitors—drugs that eliminate the immune system’s natural brakes—to boost the body’s immune response from a vaccine. What’s more, he says, the reverse may be true, too: “Using a vaccine to generate a stronger response could make it possible for more people to benefit from the checkpoint inhibitors.”
Lifting the Blockade
Over the years, immunologists have spent a lot of time and energy trying to understand how to turn on the various “go” signals that can rev up the immune system in the face of cancer. But recent studies have shed light on an equally important part of the picture: the “brake” signals that hold the immune system back and keep it from going after cancer cells. Experiments in mice in the mid-1990s showed that a protein called CTLA-4, found on the surface of T cells, acts like a brake by preventing the cells from attacking tumors. The findings eventually led to the development of the drug Yervoy (ipilimumab), a monoclonal antibody that binds to the CTLA-4 protein and blocks it from applying that brake.
“That was a turning point in the field,” says Dranoff of Dana-Farber. The drug, developed by Bristol-Myers Squibb and approved by the FDA in 2011 for the treatment of metastatic melanoma, was the first medicine ever to improve overall survival in patients with advanced forms of the disease; in a phase III trial, half of those taking the drug were still alive after 10 months—nearly four months longer than the median survival for patients given another therapy. A recent analysis presented at the European Cancer Conference in September 2013 found that 22 percent of more than 1,800 patients who took Yervoy survived three years or more; some are still alive after 10 years.
Until Yervoy was approved by the FDA, patients with metastatic melanoma had few, if any, options. “Having been in the field of melanoma oncology at that point for about 10 years, we were desperate for something that worked,” recalls Wolchok, who helped lead two of the phase III trials that led to Yervoy’s approval.
Spurred by the drug’s success, university researchers are working with major drug companies to develop other so-called checkpoint inhibitors—drugs that lift the brakes on the immune system—such as antibodies that target the proteins PD-1 and PD-L1, which have also been found to block T cells’ activity. “It’s a paradigm shift. We’re no longer giving medicines that directly attack the tumor in terms of its growth rate,” says Wolchok. “We are giving medicines that liberate the immune system from inhibitory influences.”
Antoni Ribas, an oncologist at the University of California, Los Angeles’ Jonsson Comprehensive Cancer Center, recently led a phase I study of a PD-1–blocking drug, called MK-3475, which was developed by Merck. Of the 135 patients with advanced melanoma who received the drug, 38 percent saw their tumors significantly shrink or completely disappear. The response rate was even higher—52 percent—among the patients who received the highest dose of the drug. About 80 percent of those who responded initially were still responding to treatment nine to 18 months later, when the analysis was published in the July 11, 2013, issue of the
New England Journal of Medicine (NEJM).
In some cases, combining two checkpoint inhibitors might be even more effective than taking either drug alone. In the same issue of the
NEJM, Wolchok and his colleagues reported encouraging results from a phase I study suggesting that a combination of Yervoy and an anti–PD-1 drug called nivolumab might cause tumors to shrink faster and in more people than either drug alone. Phase II and phase III trials of the drug combination are now enrolling patients.
Currently dozens of trials are underway as companies race to bring new checkpoint inhibitors to market—and not just for treating melanoma, but for a whole range of common cancers. Last summer Suzanne L. Topalian, a cancer immunologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, reported results from a phase I nivolumab study showing that 31 percent of patients with melanoma, 29 percent of patients with renal cell carcinoma, and 16 percent of patients with non–small cell lung cancer who took the drug saw their tumors shrink or disappear altogether. Bristol-Myers Squibb, the drug’s developer, now has several phase III trials testing the drug in patients with solid tumors. Similarly, Merck is testing its own anti–PD-1 drug in patients with lymphomas, non–small cell lung cancer and other solid tumors, including gastric and head and neck cancers—as well as triple-negative breast cancer, which lacks the three types of molecular receptors targeted by some of the most effective breast cancer drugs.
Though checkpoint inhibitors have received a lot of support from drug manufacturers, investment in adoptive immunotherapy has been slow. “Pharmaceutical companies want drugs they can take off of a shelf and ship around in a vial,” says Rosenberg. “They don’t care if they spend half a billion dollars developing the first vial, so long as they can make the second vial for a buck.” With adoptive immunotherapy, however, researchers have to create a new drug for every patient using the patient’s own cells. That level of complexity has been a deterrent for many drug and biotech firms, says Rosenberg.
However, some are not dissuaded. In August 2012, the drug company Novartis and the University of Pennsylvania joined forces to commercialize Carl June’s genetically modified T cells. The company has licensed the technology and is setting up large multicenter international trials to test the therapy in patients with leukemia. Novartis, in collaboration with the university’s scientists, is also focusing on the development and manufacture of modified T cells. “The CARs that we use need to be manufactured in an automated way,” says June. “That’s the issue that needs to be solved before this can have widespread use.”
Another big question is whether immunotherapies could be effective treatments for patients with earlier stage cancers. Researchers also want to determine whether these patients might experience fewer side effects—such as high fevers, breathing difficulties and kidney abnormalities—compared with patients with more advanced disease. “The tumor as it breaks down releases a lot of DNA and it can actually clog up the kidneys and you can get kidney failure,” says June. “And that’s proportional to how much tumor you’re killing.” Studies in mice, he says, suggest that the side effects could be much less in patients with fewer cancerous cells.
With that in mind, T cell therapy could become an outpatient treatment for leukemia patients with early stage disease, says June. In that hypothetical setting, patients would first receive an initial course of chemotherapy or a targeted drug to destroy as much of the cancer as possible. Then doctors would infuse the patients with genetically modified T cells to wipe out the cancer. “The toxicity would be less and it would cost less to treat people up front,” he says. “That’s where we’re trying to go.”
The percentage of cancer patients who have benefited from immunotherapies remains small, and it’s not yet entirely clear why some patients respond to the treatments and others don’t. But with dozens of clinical trials underway and collaborations between drug companies and universities growing, many have high hopes for the therapies. “This is a field that has gone from being almost non-existent to being one of the most prominent drug development areas in oncology,” says Ribas. “I think it will produce some of the most impacting classes of drugs in the next several years.”
For Meyer, the impact that cancer immunotherapy has had on her life cannot be overstated. Now 64, Meyer has had no signs of cancer for the last five years. She has become a patient advocate and works closely with melanoma patients through the Yale Specialized Programs of Research Excellence (SPORE) in Skin Cancer. Since her diagnosis, two of her children have gotten married, and she now has two grandchildren. “Had I not had this immunotherapy treatment, I wouldn’t have been around to see them,” she says. “It’s very powerful.”
March 28, 2014