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Could Immunotherapy Lead the Way to Fighting Cancer – Robin Marantz

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In the morning of June 24, 2014, a Tuesday, Vanessa Johnson Brandon awoke early in her small brick house in North Baltimore and felt really sick. At first, she thought she had food poisoning, but after hours of stomach pain, vomiting and diarrhea, she called her daughter, Keara Grade, who was at work. “I feel like I’m losing it,” said the woman everyone called Miss Vanessa. Keara begged her to call an ambulance, but her mother wanted to wait until her husband, Marlon, got home so he could drive her to the emergency room. Doctors there took a CT scan, which revealed a large mass in her colon.

Hearing about the mass terrified her. Her own mother had died of breast cancer at the age of 56. From that point on, Miss Vanessa, then 40, became the matriarch of a large family that included her seven younger siblings and their children. Because she knew how it felt to have a loved one with cancer, she joined a church ministry of volunteers who helped cancer patients with chores and doctor visits. As she prepared meals for cancer patients too weak to cook for themselves, she couldn’t know that the disease would one day come for her, too.

The ER doctors told Miss Vanessa she wouldn’t get the results of follow-up tests—a colonoscopy and a biopsy—until after the July 4 weekend. She had to smile her way through her own 60th birthday on July 6, stoking herself up on medications for nausea and pain to get through the day.

At 9:30 the next morning, a doctor from the Greater Baltimore Medical Center called. He didn’t say, “Are you sitting down?” He didn’t say, “Is there someone there with you?” Later Miss Vanessa told the doctor, who was on the young side, that when he delivers gut-wrenching news by telephone, he should try to use a little more grace.

It was cancer, just as Miss Vanessa had feared. It was in her colon, and there also was something going on in her stomach. The plan was to operate immediately, and then knock out whatever cancer still remained with chemotherapy drugs.

Thus began two years of hell for Miss Vanessa and her two children—Keara, who is now 45, and Stanley Grade, 37—who live nearby and were in constant contact with their mother and her husband. The surgery took five hours. Recovery was slow, leading to more scans and blood work that showed the cancer had already spread to the liver. Her doctors decided to start Miss Vanessa on as potent a brew of chemotherapy as they could muster.

Every two weeks, Miss Vanessa underwent three straight days of grueling chemo, administered intravenously at her home. Keara and her two teenage sons came around often to help out, but the older boy would only wave at Miss Vanessa from the doorway of her bedroom as he rushed off to another part of the house. He just couldn’t bear to see his grandmother so sick.

Miss Vanessa powered on for 11 months, visualizing getting better but never really feeling better. Then, in July 2015, the doctor told her there was nothing more he could do for her.

“My mom was devastated,” Keara says. Keara told her mother not to listen to the doctor’s dire prediction. “I said to her, ‘The devil was a liar—we are not going to let this happen.’”

So Keara—along with Miss Vanessa’s husband, brother and brother’s fiancée—started Googling like mad. Soon they found another medical center that could offer treatment. But it was in Illinois, in the town of Zion—a name Miss Vanessa took as a good omen, since it was also the name of her 5-year-old grandson. In fact, just a few days earlier little Zion had asked his grandmother if she believed in miracles.

The family held a fund-raiser for Stanley to get on a plane to Chicago with his mother every two weeks, drive her to Zion and stay with her at the local Country Inn & Suites hotel for three days of outpatient chemotherapy. It felt like a replay of her treatment in Baltimore—worse, since the drugs were delivered in a hotel instead of in her bedroom, and the chemotherapy caused nerve damage that led to pain, tingling and numbness in Miss Vanessa’s arms and legs.

And then, in May 2016, the Illinois doctor, too, said there was nothing more he could do for her. But at least he offered a sliver of hope: “Go get yourself on a clinical trial.” Weeks later, desperate, Miss Vanessa and Keara grew hopeful about a treatment involving mistletoe. They attended an information session at a Ramada extolling the plant extract’s anti-cancer properties. But when they learned that it would cost $5,000 to enroll, they walked out dejected.

Finally, Miss Vanessa’s husband stumbled onto a website for a clinical trial that seemed legit, something underway at the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, just down the road from their home. This new treatment option involved immunotherapy, something markedly different from anything she had gone through. Rather than poisoning a tumor with chemotherapy or zapping it with radiation, immunotherapy kills cancer from within, recruiting the body’s own natural defense system to do the job. There are a number of different approaches, including personalized vaccines and specially engineered cells grown in a lab. (See “A Cancer Vaccine?” and “A DNA-Based Attack”)

The trial at Hopkins involved a type of immunotherapy known as a checkpoint inhibitor, which unlocks the power of the immune system’s best weapon: the T-cell. By the time Miss Vanessa made the call, other studies had already proved the value of checkpoint inhibitors, and the Food and Drug Administration had approved four of them for use in several cancers. The Hopkins researchers were looking at a new way of using one of those drugs, which didn’t work at all for most patients but worked spectacularly well for some. Their study was designed to confirm earlier findings that had seemed almost too good to be true.

“With the very first patient who responded to this drug, it’s been amazing,” says Dung Le, a straight-talking Hopkins oncologist with long dark hair and a buoyant energy. Most of her research had been in desperately ill patients; she wasn’t used to seeing her experimental treatments do much good. “When you see multiple responses, you get super-excited.”

Immunotherapy is poised to become the standard of care for a variety of cancers. The work being done now is forcing a reconsideration of basic tenets of clinical oncology—for instance, whether surgery should be a first line of treatment or should come after drugs like Keytruda.

Many questions still remain. Elizabeth Jaffee, a member of the “cancer moonshot” panel convened by then-Vice President Joseph Biden in 2016, says she’s conscious of the danger of overselling a treatment. While the effect of checkpoint inhibitors can be “exciting,” she says, “you have to put it in perspective. A response doesn’t mean they’re cured. Some may have a year of response,” but the cancer might start growing again.

When Miss Vanessa paid her first visit to Le in August 2016, the physician explained that not every patient with advanced colon cancer qualified for the trial. Investigators were looking for people with a certain genetic profile that they thought would benefit the most. It was a long shot—only about one person in eight would fit the bill. If she had the right DNA, she could join the trial. If she didn’t, she would have to look elsewhere.

About a week later, Miss Vanessa was in her kitchen, a cheery room lined with bright yellow cabinets, when her telephone rang. Caller ID indicated a Hopkins number. “I didn’t want anyone else to call you but me,” said the study’s principal investigator, Daniel Laheru. He had good news: her genes “matched up perfectly” with the criteria for the clinical trial. He told her to come in right away so they could get the blood work done, the paperwork signed and the treatment started. Miss Vanessa recalls, “I cried so hard I saw stars.”

The trial was part of a string of promising developments in immunotherapy—an apparent overnight success that was actually more than 100 years in the making. Back in the 1890s, a New York City surgeon named William Coley made a startling observation. He was searching medical records for something that would help him understand sarcoma, a bone cancer that had recently killed a young patient of his, and came upon the case of a house painter with a sarcoma in his neck that kept reappearing despite multiple surgeries to remove it. After the fourth unsuccessful operation, the house painter developed a severe streptococcus infection that doctors thought would kill him for sure. Not only did he survive the infection, but when he recovered, the sarcoma had virtually disappeared.

Coley dug deeper and found a few other cases of remission from cancer after a streptococcus infection. He concluded—incorrectly, it turned out—that the infection had killed the tumor. He went around promoting this idea, giving about 1,000 cancer patients streptococcus infections that made them seriously ill but from which, if they recovered, they sometimes emerged cancer-free. He eventually developed an elixir, Coley’s Toxins, which was widely used in the early 20th century but soon fell out of favor as radiation and then chemotherapy began to have some success in treating cancer.

Then, in the 1970s, scientists looked back at Coley’s research and realized it wasn’t an infection that had killed the house painter’s tumor; it was the immune system itself, stimulated by the bacterial infection.

In a healthy body, T-cells activate their weaponry whenever the immune system detects something different or foreign. This might be a virus, a bacterium, another kind of disease-causing agent, a transplanted organ—or even a stray cancer cell. The body continuously generates mutated cells, some of which have the potential to turn cancerous, but current thinking is that the immune system destroys them before they can take hold.

Once scientists recognized the cancer-fighting potential of the immune system, they began to look for ways to kick it into gear, hoping for a treatment that was less pernicious than chemotherapy, which often uses poisons so toxic the cure may be worse than the disease. This immune-based approach looked good on paper and in lab animals, and showed flashes of promise in people. For instance, Steven Rosenberg and his colleagues at the National Institutes of Health’s National Cancer Institute made headlines when they removed a patient’s white blood cells, activated them in the lab with the immune system component known as interleukin-2, and infused the cancer-fighting cells back into the patient in hopes of stimulating the body to make a better supply of cancer-fighting cells. Rosenberg ended up on the cover of Newsweek, where he was hailed for being on the cusp of a cancer cure. That was in 1985.

The FDA did approve interleukin-2 for adults with metastatic melanoma and kidney cancer. But immunotherapy remained mostly on the fringes for decades, as patients continued to go through rounds of chemotherapy and radiation. “We’ve been curing cancer in mice for many, many years . . . but the promise was unfulfilled for a very long time in people,” says Jonathan Powell, associate director of the Bloomberg-Kimmel Institute at Hopkins.

Meanwhile, Topalian is continuing to work with Hopkins experts in genetics, metabolism, bioengineering and other areas. One of her colleagues, Cynthia Sears, recently received a grant to study biofilms—the colonies of bacteria that grow in the colon and can either promote or prevent cancer growth. Sears is looking at how a particular “tumor microbial environment” affects the way a patient responds—or fails to respond—to cancer immunotherapy.

“The immune system is the most specific and powerful killing system in the world,” says Pardoll, summing up the state of immunotherapy in early 2018. “T-cells have an amazingly huge diversity, and 15 different ways to kill a cell. The basic properties of the immune system make it the perfect anti-cancer lever.” But science won’t be able to fully mobilize that system without the help of myriad specialists, all working from different angles to piece together the incredibly complex puzzle of human immunity.
Indeed, many cancer experts lost faith in the approach over the next decade. “Nobody believed in immunotherapy except our own community,” says Drew Pardoll, the director of the BKI. The lack of support was frustrating, but Pardoll says it did have one salutary effect: It made immunotherapy more collegial and less back-biting than a lot of other fields of science. “When you’re a little bit ostracized I think it’s just a natural part of human nature…to sort of say, ‘Well, look, our field is going to be dead if we don’t work together, and it shouldn’t be about individuals,’” Pardoll said. He calls the recent explosion of successes “sort of like Revenge of the Nerds.”

In keeping with this collaborative spirit, immunotherapy researchers from six competing institutions have formed a cover band known as the CheckPoints, which performs at the annual meeting of the American Society of Clinical Oncology and in other venues. The band’s harmonica player, James Allison of the M.D. Anderson Cancer Center in Houston, helped set immunotherapy on its current course with his work on checkpoint inhibitors in 1996, when he was at Berkeley. He was the first to prove that blocking the checkpoint CTLA-4 (shorthand for “cytotoxic T-lymphocyte antigen”) with an antibody would generate an anti-tumor response. As Pardoll puts it, once Allison demonstrated that first checkpoint system, “we had molecular targets. Before that, it was a black box.”

The checkpoint system, when it’s working as it should, is a simple one: invader is detected, T-cells proliferate. Invader is destroyed, T-cells are deactivated. If T-cells were to stay active without an invader or a rogue cell to fight, they could create collateral damage to the body’s own tissues. So the immune system contains a braking mechanism. Receptors on the surface of the T-cells look for binding partners on the surfaces of other cells, indicating that those cells are healthy. When these receptors find the proteins they’re looking for, they shut the T-cells down until they spot a new invader.

Cancer cells are able to do their damage partly because they co-opt these checkpoints—in effect, hacking the immune system by activating the brakes. This renders the T-cells impotent, allowing the cancer cells to grow unimpeded. Now scientists are figuring out how to put up firewalls that block the hackers. Checkpoint inhibitors deactivate the brakes and allow the T-cells to get moving again. This lets the body kill off the cancer cells on its own.

Suzanne Topalian, who is Pardoll’s colleague at the Bloomberg~Kimmel Institute (and also his wife), played a key role in identifying another way the immune system could be used to fight cancer. After working as a fellow in Rosenberg’s lab, she became the head of her own NIH lab in 1989 and moved to Johns Hopkins in 2006. At Hopkins, she led a group of investigators who first tested drugs blocking the immune checkpoint receptor PD-1—short for “programmed death-1”—and the proteins that trigger it, PD-L1 and PD-L2.

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