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Unleashing the Immune System

New treatments that harness the power of the immune system are taking aim at many common cancers. By Alexandra Goho

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.

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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.


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