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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