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You Curing You

By Deborah Rudacille
Imagine if your body could fight cancer the way it fights a cold? Johns Hopkins researchers are discovering new therapies to trigger your immune system’s response in the fight against cancer.
In November 2008, cancer researcher Drew Pardoll was rushing to catch a flight to Paris, where he would attend a scientific meeting. Pardoll, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins Medicine, was conducting research on cancer cures through a cutting-edge approach: immunotherapy. Pardoll and his colleagues at Johns Hopkins had developed a vaccine to stimulate the immune system in the fight against malignant cells. The drug was meant to prod the immune system into battling cancer in the same way the body fights viral and bacterial infections—by activating T cells to launch an attack on the invader.
Just before boarding the plane, Pardoll checked his email and read a message that knocked him flat. The biotech company running a clinical trial on the drug had pulled the plug. Preliminary data determined that not enough patients were showing improvement. 
Pardoll wasn’t the only one to have a trial scrapped. Other cancer vaccines were producing mixed results, and pharmaceutical and biotech companies—and even some clinical oncologists—were becoming convinced that the vaccine approach was a dead end. “They closed the trial,” Pardoll says, “and it was not only the lowest point for me personally but a low point for the field.”
Two months later, everything changed. Just weeks after their trial came to an abrupt halt, Pardoll and his colleagues made a breakthrough in understanding why cancer vaccines saw mixed results. They discovered a protein pathway that’s integral in orchestrating our body’s immune response. Cancers can mutate quickly, in effect turning themselves into moving targets. But Pardoll’s group discovered an even more important weapon that cancer wielded: the ability to immobilize our immune system by hijacking checkpoint proteins that are integral to our immune response. This presented a whole new set of possibilities.
A healthy immune system is able to recognize “nonself” pathogens of various kinds, such as bacteria, viruses, and parasites, and destroy them without harming healthy tissue or “self.” The immune system responds to potentially harmful substances by recognizing and responding to antigens—usually proteins—on the surface of “nonself” cells. T cells, a type of white blood cell, play a critical role by attacking infected cells directly and helping orchestrate the overall immune response. 
As T cells develop, they normally learn how to distinguish between “self” and “nonself” tissues and substances.  They also learn to remember antigens so that the immune system can respond faster and more efficiently the next time it encounters the same thing. Sometimes this process goes awry. Immune cells can overreact to benign substances like grasses, dust mites, or pet dander, and suddenly you’re hit with allergies. In autoimmune diseases like lupus, the immune system goes haywire, attacking the body’s own cells, tissues, and organs. But normally, the immune system works efficiently to protect the body from disease. 
In theory, T cells—the infantry of the immune system—ought to recognize cancer cells as “nonself” and attack the invader. But they don’t. Figuring out why has taken decades of research. “Cancers contain a lot of mutations that have never been seen before by the immune system, so they should be really strong stimulants of the immune system,” says Suzanne Topalian, professor of surgery and director of the melanoma program in the Johns Hopkins Kimmel Cancer Center. Topalian is one of Pardoll’s closest collaborators and also his spouse. 
Cancer cells are cunning adversaries, capable of signaling to immune cells that they are “self” and thus pose no danger. It’s a bit like the Jedi mind trick Obi-Wan Kenobi uses to thwart Imperial Stormtroopers in Star Wars—“these are not the droids you are looking for”—enabling the good guys to evade detection. Except in this case, the cancer cells are the bad guys and by cloaking themselves, they manage to multiply while T cells stand by like befuddled Imperial Stormtroopers. “The immune cells are still there, poised to attack, but the cancer cells are telling those immune cells to pass them by,” Topalian says. 
Back in 2008 when Pardoll got the bad news about the cancer vaccine, he and Topalian were trying to figure out how tumors were able to trick T cells into ignoring them. They and other cancer researchers were looking for checkpoint proteins that tell immune cells when to switch off. Under normal circumstances, checkpoints act as brakes on immune response, preventing T cells from attacking healthy tissue. Cancer cells, they found, somehow co-opt checkpoints to do their bidding, not just tricking T cells into ignoring their presence but sometimes even providing growth factors that help tumors expand.
They knew that some types of cancer—like ovarian and melanoma—kick off an immune response, activating T cells, while others—like prostate cancer—don’t. In the cancers with no immune response, a vaccine would come in handy, by mustering those T cells to fight the cancer. In either case, while the T cells are trying to get to work, cancer cells that have hijacked the immune checkpoints shield themselves against immune attack. 
The Johns Hopkins researchers identified a particular checkpoint protein called PD-1, which existed in melanoma, lung, ovarian, and other types of cancer samples. This protein and its partners normally suppress the immune system by limiting the activity of T cells during an immune response, thus protecting healthy tissue. Cancer cells had commandeered it for their own use. PD-1 binds with certain molecules that are displayed on the surface of cancer cells.
The researchers discovered that if they could switch off either this protein or its partners, the T cells would waken from their stupor, attack the cancer cells, and shrink tumors.  “Literally within two months of the announcement that the company developing our cancer vaccine was closing the trial, we saw our first clinical response [to the blockers],” Pardoll says. 
A few patients with advanced cancers, who had not responded to any other type of treatment, showed measurable improvement after being treated with a drug that blocked PD-1. Pardoll and Topalian tried not to get too excited. They’d seen this kind of thing before with vaccine trials. But as the number of patients responding to PD-1 blockers began to grow, they allowed themselves some hope. They saw regression of tumors in people with advanced colon cancer, melanoma, kidney cancer, and lung cancer. “We’d been through so many emotional roller coasters that we’d trained ourselves not to get excited,” says Pardoll. “But it turned out that this was the real deal.” Today, there is “an entire pipeline of new drugs, either in clinical testing or about to be, that target these immune checkpoints,” says Topalian. 
Since not all tumors respond to PD-1 blockers, Hopkins researchers developed a test to determine which patients would be most likely to benefit. “It’s now been borne out in thousands of patients that if your tumor expresses [certain attributes] before treatment, you are three to four times more likely to respond to the drug,” says Topalian. 
Researchers are now investigating why some types of cancer, such as prostate cancer, do not respond to checkpoint blockers at all. That may be because these cancers are nonimmunogenic, meaning they do not induce an immune response in the first place. “There are some cancers that naturally attract T cells, such as melanoma, lung, and kidney cancers. Those are the ones that respond to immune-modulating agents,” says Elizabeth Jaffee, professor of oncology and deputy director of the Johns Hopkins Kimmel Cancer Center. “But what we’re seeing is that some cancers, called nonimmunogenic cancers, actually don’t have T cells. They need to be induced.” 
an illustration of germs attacking healthy cells
That’s where vaccines come in, recruiting T cells to the tumor site. A two-step process—a vaccine plus a checkpoint blocker—will likely be needed when tumors don’t naturally induce an immune response. Researchers compare it to pressing on the accelerator (vaccine) and then releasing the brake (checkpoint blocker) on the immune system.
Jaffee, who began vaccine research in 1990, has been testing this two-step process on patients on one of the deadliest cancers: pancreatic. Two weeks before surgery, she gave a small group of patients a vaccine to stimulate T cell production. “Some patients who’ve received the vaccine have gone on to long-term survival,” she says. “Our next step is to combine vaccine with an anti-PD-1 signaling agent and prove we can activate the majority of patients not activated with vaccine alone.” 
She and her team are currently involved in three clinical trials to test this model, one of which is nearing final stages. “We should have an answer in about a year on whether or not it is approved for treatment of pancreatic cancer.”

The next frontier in this research involves tailoring immunotherapy to the individual patient. Individual tumors can contain up to 500 genetic mutations, Jaffee says, making cancer unique to each person. It’s analogous to a fingerprint; no two cancers are exactly the same. Imagine being able to target cancer antigens specific to a patient. Homing in on antigens responsible for tumor growth within a particular patient, and activating T cells to fight that individual’s cancer antigens, has the potential to revolutionize cancer treatment. 

Even a few years ago, this would have been a pipe dream. Determining the complete DNA sequence of a patient’s cancer cells would have been prohibitively expensive. But the cost of whole genome sequencing has been rapidly dropping; it may soon be possible for physicians to take a small amount of tissue in a biopsy, run a DNA analysis, and then activate T cells to strike targets native to that individual. “We think we might be able to bring this to clinical trials in a couple of years,” Jaffee says. 
Now imagine bioengineering T cells that can attack multiple targets at once. Jonathan Schneck, professor in the departments of Pathology, Medicine and Oncology at Johns Hopkins, has developed a new technology that may enable clinicians to pursue multiple mutations in cancer cells and turn the immune response on and off at will using nanoparticles.
Nanoparticles are particles or beads that are used to ferry drugs, proteins, and genes into cells. Their size enables them to pass through cell membranes and deliver their payloads without disrupting normal function. Schneck and his team are experimenting with a technique that will allow them to take T cells out of an individual’s body, stimulate them to respond to particular antigens, and then return them to the patient (via nanoparticle) to strike at multiple targets. 
“When you target only one moiety—one protein, one cancer antigen—with an immunotherapy, you can put a temporary stop on the tumor, but the tumor is likely to figure out a way to work around that,” Schneck says. But if you tweak T cells to hit multiple antigens, you have a much better chance of defeating the cancer. “The technology is broadly applicable to immunotherapy for cancer, for infectious disease, for autoimmune diseases,” says Schneck. “It’s really an artificial conductor for the immune system.”
The technology, which has not yet been tested in humans, appears to increase the number of personalized T cells. Those activated T cells have in turn been shown to attack tumors and lead to tumor shrinkage in experiments with mice. “We’re just one or two steps away from clinical trials,” Schneck says. 

Yet another technology—stem cell engineering—has promise for patients with diseases of the bone marrow and blood, as well as some solid cancers. Bone marrow transplant—an early form of cancer immunotherapy—combined with aggressive chemotherapy has already increased survival rates of people with leukemia and lymphoma. “Back in the 1970s, less than 10 percent would survive,” says Elias Zambidis, a pediatric oncologist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. “Now there is a standard survival rate of 90 percent.”

Bone marrow transplant has improved survival in two ways. First, it enables oncologists to give patients extremely high doses of chemotherapy that they would not otherwise survive because it would kill off their entire blood system. After chemotherapy, a bone marrow transplant by a compatible donor regenerates marrow. “By transplanting that blood system [via bone marrow transplant], you rescue them,” Zambidis says. But chemotherapy alone doesn’t really cure leukemia—it only puts the disease into remission. “Most leukemias, especially very aggressive ones, come right back like a boomerang,” he says.
It’s the immunotherapy aspect of bone marrow transplant that actually cures the disease. Here’s how it works. Marrow is the soft tissue inside bones that produces blood-forming cells, including the lymphocytes of the immune system. Marrow from a compatible donor contains T cells that recognize and attack the recipient’s cancer cells. The problem, Zambidis says, is that “friendly fire” from those donor T cells can also attack healthy tissue. This is called graft-versus-host disease, and it can make the recipient very sick. But if they survive the assault, they are often cured. “The art of bone marrow transplant is harnessing that beast so it attacks the leukemia while not attacking you too much,” says Zambidis.
“Our contribution to immunotherapy would be to create an entirely new blood or immune system that is patient-specific and that would come from a single skin cell.” 
The challenge with bone marrow transplant is that good matches are hard to find and the process is uncomfortable for donors and recipients. A far better option would be to take a small sample of blood or skin from the patient, genetically engineer the cells in the sample back to a primitive state, and then reprogram them to become blood and immune cells. These primitive cells are called pluripotent stem cells because they have the potential to become any type of cell in the body. They are akin to cells found in very early stage human embryos, five days after sperm and egg meet.  Learning how to reverse adult cells to a pluripotent state, and then coaxing them into becoming fully functioning blood or heart or pancreatic or immune cells, is still a work in progress. 
Zambidis and other stem cell researchers have already created beating heart cells and other marvels from induced pluripotent stem cells. They have not yet pulled off this trick with immune cells. But the possibility is compelling.  “Our contribution to immunotherapy would be to create an entirely new blood or immune system that is patient-specific and that would come from a single skin cell,” he says. 
When asked how long it will take to bring this to the clinic, Zambidis estimates five to 10 years. “Perhaps faster.”
Considering the great advances that immunotherapy research has made since that setback in 2008, Pardoll is encouraged by the current state of the science. “Immunotherapy is here to stay,” he says. The scientific community, he adds, is primed to unearth even greater possibilities. “I think we’ve mined about 5 percent of what the immune system can do.”  
Illustration of germs and microbes creating antibodies
Illustrations by John Hersey
Cancer cells are cunning adversaries, capable of signaling to immune cells that they are “self” and thus pose no danger. 

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