2017 8 18 - WSJ - How HIV Became a Cancer Cure

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2017 8 18 - WSJ - How HIV Became a Cancer Cure

Postby tcphillips » Mon Aug 28, 2017 7:39 pm

How HIV Became a Cancer Cure
The immunologist behind the revolutionary new treatment set to win approval from the FDA.
By Allysia Finley
Aug. 18, 2017 5:34 p.m. ET


When Ben Franklin proposed in 1749 what eventually became the University of Pennsylvania, he called for an academy to teach “those Things that are likely to be most useful.” Today the university lays claim to having incubated the world’s biggest cancer breakthrough. In 2011, a team of researchers led by immunologist Carl June, a Penn professor, reported stunning results after genetically altering the T-cells of three patients with advanced chronic lymphocytic leukemia, a cancer that affects white blood cells.

The patients had failed to respond to many different traditional therapies. Yet two of the three patients experienced miraculous recoveries after Dr. June and his team gave them infusions of their own doctored white blood cells. Seven years later they remain cancer-free. The third patient died after showing improvements, though might have been saved had the treatment begun earlier.

The results, published in the New England Journal of Medicine in August 2011, opened the field of cancer immunotherapy. “It was a tipping point,” recalls the 64-year-old Dr. June. “There was an amazing outpouring because we showed for the first time that it could work.”

And it worked spectacularly well—more than 90% of pediatric patients with acute lymphoblastic leukemia in a subsequent clinical trial went into remission after being infused with Dr. June’s CAR T-cells (the acronym stands for “chimeric antigen receptor”). Last month an advisory committee of the Food and Drug Administration unanimously approved the therapy to treat acute lymphoblastic leukemia. The FDA is likely to give final approval within weeks.
Illustration: Zina Saunders

Dr. June sat down at his office at Penn Medicine’s Smilow Center for Translational Research—near where then-Vice President Joe Biden launched the U.S. government’s cancer “moon shot” initiative in 2016—to discuss the development of CAR T-cell therapy, its potential to cure other cancers, and the challenges ahead—both scientific and regulatory.

“Cancer immunotherapy isn’t a new idea,” he says. “It’s been around for 100 years, but everybody has always snickered at it because it had always failed, and we didn’t understand the complexity.” Scientists once thought cancers were usually caused by viruses: “It wasn’t until the 1970s that we understood that most cancers are caused by mutations.”

Dr. June graduated from the U.S. Naval Academy in 1975 and was trained as an oncologist. But while serving in the Navy Medical Corps, he studied infectious diseases. “My first research was with HIV,” he says. Later he would use the virus as a tool to treat patients.

The characteristic that makes HIV so deadly—it incorporates its DNA directly into host cells’—also makes it pliable for gene therapy. In the 1990s, Dr. June’s lab at Penn experimentally treated HIV patients using a re-engineered form of the virus. The researchers used modified HIV cells as a tool to alter the DNA of T-cells, which prevented the virus from replicating. Dr. June calls the cut-and-paste job “an anti-HIV molecular scissors.”

About 15 years ago he first considered using HIV to kill cancer cells. At the time, he says, “the rest of the community that did cancer immunotherapy had all been using viruses out of mice, called gammaretroviruses. And it turns out the HIV works better with human T-cells than the mouse virus does.”

Dr. June pauses for a quick tutorial on the human immune system: “There are two major cell types in our acquired immune systems that distinguish us from flies, and those are B-cells and T-cells.” T-cells are a sort of offensive weapon, destroying viruses and bacteria. B-cells are more like a shield. They produce antibodies that detect and swat down foreign invaders based on unique molecular characteristics. A CAR T-cell is a “chimera”—Greek for a fusion of two animals. It combines the “killing machinery” of T-cells with the precise antibody targeting of B-cells.

A CAR T-cell is designed to bind to a particular site on the cancer cell. That means, unlike with chemotherapy and radiation, other cells in the body aren’t damaged when patients receive CAR T-cell infusions. The result is fewer unpleasant long-term side effects.

When a CAR T-cell binds to the target, the immune system responds the same way it does to a virus: T-cells kill the cancerous cells and then proliferate. Once all the cancer is destroyed, CAR T-cells remain on what Dr. June calls “memory level”: “They are on surveillance, we now know, for at least seven years.”

There is, however, a hitch or two. After being cured, patients must receive blood infusions every few months to prevent their immune systems from killing off their B-cells. And about a third of patients undergoing treatment with CAR T-cells experience a violent immune-system reaction known as cytokine-release syndrome. When cancer cells die, they release inflammatory proteins called cytokines that can cause high fevers and leave patients comatose.

Cytokine-release syndrome almost ended the therapy in its infancy. In 2012, Dr. June’s first pediatric patient, 6-year-old Emma Whitehead, developed a 106-degree fever and experienced multiple organ failure. “We thought she was going to die,” he recalls.

A blood analysis showed high levels of the cytokine interleukin-6, or IL-6. “I happened to know because of my daughter’s arthritis that there was a drug that could target IL-6—that had never been used in oncology,” Dr. June recalls. Fortunately, the children’s hospital where Emma was being treated had the medication, Tocilizumab, on hand. “We wouldn’t have had it at the adult hospital because it wasn’t approved at that point for adult conditions.”

Within hours of receiving the drug, Emma awoke from her coma. “It was literally one of those Lazarus conditions,” Dr. June says. Eight days after receiving the CAR T-Cell injection, she went into remission. Two weeks later, she was cancer-free. She’s now 12 and thriving.

Tocilizumab “saved the field” as well as the girl, Dr. June says. “If the first patient dies on a protocol and nobody’s been cured, you’re over.” Regulators, he adds, always “err on the side of caution.” That irks him, since most of his patients would die without the experimental treatments: “Our FDA regulations are made so that you can never have more than about 30% of people get sick with serious side effects. I think we don’t have enough leeway for side effects when you have a potentially curative therapy.”

Our conversation sticks to science, not politics, but Dr. June seems to be no right-winger. A sign hanging in his office reads “Bicycling: A Quiet Statement Against Oil Wars.” Still, you don’t have to be a conservative to see fault in government regulations. Dr. June blames two episodes in particular for the FDA’s excessive caution: the “Cutter incident,” in which a defective polio vaccine caused thousands of cases of the disease in the 1950s; and the drug Thalidomide, which was used during the 1950s to treat morning sickness and caused thousands of serious birth defects abroad.

Aversion to risk helps explain why the U.S. so frequently ends up leading from behind on cancer research. Before Dr. June’s successful early protocols, the National Cancer Institute had shown very little interest. “When we started in 2010, there were only three groups in the world trying to treat cancer with CAR T-cells,” he says. “Now there are over 200 trials.”

Some of those are in the U.S., but more are taking place in China. “There’s a lot more people there, so you can do a lot more trials,” Dr. June says. “But they also put more of their GDP into medical therapy, particularly CAR T-cells.” Beijing’s drug-approval process is easier, too.

As private and public funding increase, Dr. June expects breakthroughs to come more rapidly. Within a decade, he believes there will be a pathway to curing every blood and bone-marrow cancer. Solid tumors are trickier because their cell walls aren’t easily permeated, and they can contain many different mutations. One of the hardest cancers to treat, he says, is pancreatic because its genetic marker is hard to target: “It’s like a piece of grease—it’s slippery.”

Glioblastoma, the brain cancer with which Sen. John McCain was recently diagnosed, is also challenging. A recent Penn protocol targeting a receptor on brain tumors showed that the CAR T-cells successfully crossed the blood-brain barrier. “But then we found that the target was gone. That’s called tumor editing,” Dr. June says. “Patients still had a tumor, but it no longer had that target.” In other words, the tumor mutated—as bacteria do in response to antibiotics: “This is just like Darwin evolution—you have one mutation, then it divides and has two daughter cells, and the second cell may have a second mutation.”

Since a glioblastoma often consists of many different tumors, the difficulty is designing a T-cell that targets them all—or, alternatively, devising a cocktail of T-cells. “That’s what we’ve done with HIV,” Dr. June says. “People take three or four drugs, and then the virus can’t mutate and be resistant.”

He’s also confident that economic competition will spur innovation. The University of Pennsylvania has licensed its CAR T-cell treatment to Novartis , and other pharmaceutical and biotech companies are racing for their own cures. “There are at least 40 companies right now making CAR T-cells . . . and they are incentivized to make it more cheaply,” he says. “The rate of innovation is so fast, patent life is going to be irrelevant for T-cells because it will be like your phone. Every two or three years, you buy a new phone because it’s better even though the patent hasn’t gone out.”

A massive challenge will be scaling up. Currently, each patient requires a team of highly trained, specialized scientists and technicians to re-engineer his T-cells. “If you have 100,000 lung-cancer cases each year, there aren’t 100,000 Ph.D.s to grow the cells,” Dr. June says. “So it needs to be done with robotics.”

But eventually, he thinks the principles behind Moore’s law—which describes the exponential improvements in microchips—will apply in immunotherapy. “I remember when cellphones first came out, and I was thinking these are only going to be for the really rich. And now people all over Third World economies have them,” he says. “The same thing is going to happen with CAR T-cells. What we don’t know is how long that is going to take to happen. That could be 10 years from now, five years from now or 20 years from now.” He says it’s fortunate, in a way, that the initial CAR T-cell treatment was for a rare disease: “When we get something that really works, hopefully we will be able to mass-produce it. And trust me, the Chinese are good at that.”

Manufacturing T-cells at the moment is extremely expensive, and it’s unclear whether and how insurance companies will cover the costs. But the million-dollar question may be whether regulatory approvals will keep up with the technology. Dr. June is optimistic on this front. “There are now these Facebook networks of kids who had leukemia and been treating with CARs,” he says. “And the parents talk to each other faster than the medical literature can evolve.” If patients soon line up for CAR T-cells as consumers do for iPhones, the demand for access to lifesaving treatments will be hard to ignore.

Ms. Finley is an editorial writer at the Journal.

Appeared in the August 19, 2017, print edition.

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