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.
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.
