The doctors looking at Layla Richards saw a little girl with leukemia bubbling in her veins. She’d had bags and bags of chemotherapy and a bone marrow transplant. But the cancer still thrived. By last June, the 12-month-old was desperately ill. Her parents begged—wasn’t there anything?
There was. In a freezer at her hospital—Great Ormond Street, in London—sat a vial of white blood cells. The cells had been genetically altered to hunt and destroy leukemia, but the hospital hadn’t yet sought permission to test them. They were the most extensively engineered cells ever proposed as a therapy, with a total of four genetic changes, two of them introduced by the new technique of genome editing.
Soon a doctor from Great Ormond was on the phone to Cellectis, a biotechnology company with French roots that is now located on the East Side of Manhattan. The company owned the cancer treatment, which it had devised using a gene-editing method called TALENs, a way of making cuts and fixes to DNA in living cells. “We got a call. The doctors said, ‘We’ve got a girl who is out of T cells and out of options,’” André Choulika, the CEO of Cellectis, remembers. “They wanted one of the vials made during quality-control testing.”
The doctors hoped to make Layla a “special,” a patient who got the drug outside a clinical trial. It was a gamble, since the treatment had been tried only in mice. If it failed, the company’s stock and reputation could tank, and even if it succeeded, the company might get in trouble with regulators. “It was saving a life versus the chance of bad news,” Choulika says.
Cellectis began developing the treatment in 2011 after doctors in New York and Philadelphia reported that they’d found a way to gain control over T cells, the so-called killer cells of the immune system. They had shown that they could take T cells from a person’s bloodstream and, using a virus, add new DNA instructions to aim them at the type of blood cell that goes awry in leukemia. The technique has now been tested in more than 300 patients, with spectacular results, often resulting in complete remission. A dozen drug firms and biotechnology companies are now working to bring such a treatment to market.
The T cells created by Cellectis could have even broader applications. The previous treatments use a person’s own cells. But some patients, especially small children like Layla, don’t have enough T cells.
Foreseeing this problem, Cellectis had set out to use gene editing to create a more highly engineered but ultimately simpler “universal” supply of T cells made from the blood of donors. The company would still add the new DNA, but it would also use gene editing to delete the receptor that T cells normally use to sniff out foreign-looking molecules.
“The T cell has a huge potential for killing. But the thing you can’t do is inject T cells from Mr. X into Mr. Y,” Choulika says. “They’d recognize Mr. Y as ‘non-self’ and start firing off at everything, and the patient will melt down.” But if the T cells are stripped down with gene editing, like the ones that were sitting in Great Ormond’s freezer, that risk is mostly eliminated. Or so everyone hoped.
In November, Great Ormond announced that Layla was cured. The British press jumped on the heartwarming story of a brave kid and daring doctors. Accounts splashed on front pages sent Cellectis’s stock price shooting upward. Two weeks later, the drug companies Pfizer and Servier announced they would ante up $40 million to purchase rights to the treatment.
Although many of the details of Layla’s case have yet to be disclosed, and some cancer experts say the role of the engineered T cells in her cure remains murky, her recovery pointed a spotlight on “immune engineering,” and on the way that advances in controlling and manipulating the immune system are leading to unexpected breakthroughs in cancer treatment. They also could lead to new treatments for HIV and autoimmune diseases like arthritis and multiple sclerosis.
The human immune system has been called nature’s “weapon of mass destruction.” It has a dozen major cell types, including several kinds of T cells. It defends against viruses it’s never seen before, suppresses cancer (though not always), and for the most part manages to avoid harming the body’s own tissue. It even has a memory, which is the basis of all vaccines.
More than 100 years ago, the American surgeon William Coley observed that an unexpected infection could sometimes make a tumor evaporate. Subsequently, Coley injected streptococcal cultures into cancer patients and saw the tumors shrink in some cases. The finding, published in 1893, showed the immune system could confront and fight cancer—but how did it work? Until recently, the answers weren’t known, and cancer immunotherapy was seen as a failed idea.
But scientists have gradually mapped the network of molecules that govern how the immune system interacts with a tumor. And over the last few years, these insights have allowed drug companies and labs to start tinkering with the immune system’s behavior. “From 40 years and more of science, we know the general nature of the conversation between the tumor cells and the immune system,” says Philip Sharp, a biologist at MIT’s Koch Institute for Integrative Cancer Research and a recipient of the 1993 Nobel Prize in medicine. “That’s the conversation we’re trying to join in order to have a therapeutic effect. We are still at the level of a five-year-old kid. We know there are nouns, and that there are verbs. But the diversity of the vocabulary is still being mapped out.”
The most extreme of these proposals is to change the genetic instructions inside the T cell itself, something that’s become much easier using gene-editing methods like TALENs and the even newer CRISPR. Last year, the gene-editing startups Editas Medicine and Intellia Therapeutics each struck deals with companies developing T-cell-based therapeutics. “It’s the perfect setup,” says Jeffrey Bluestone, a researcher at the University of California, San Francisco. “Immune cells are machines that work pretty well, but we can make them work even better.”
Researchers are building on decades of research (and several Nobel Prizes involving immunology) that worked out many important details, including how T cells recognize invaders and go in for the kill. Seen through a microscope, these cells display almost animal--like behavior: they crawl, probe, then grab another cell and shoot it full of toxic granules. “What’s exciting is they have the ability to move all around; they’re autonomous,” says Wendell Lim, a synthetic biologist who is also at UCSF. “Immune cells talk to other cells, they deliver poisons, they can change what happens in a microenvironment, they have a memory, and they make more of themselves. I think of them as little robots.”
Lim is now breaking new ground in what he calls “synthetic immunology.” This year and last, he produced some futuristic T cells. Tested only in mice so far, the cells deploy their targeted search-and-kill behavior only if a specific drug is added—a feature that could be used to turn the cells on at specific places and times, which Lim calls “remote control.” Another T cell he designed is a two-stage affair, which kills only if it locates not one but two different markers on a cancer cell; it is like a dual authentication method for the enemy cell. Lim thinks of it as a sensing circuit or “advanced Google search.”
Such work is critical because targeting T cells to tumors of the liver, lung, or brain is dangerous, and some patients have been killed in trials. The problem has been friendly fire. So far, easy ways to target only cancer cells are lacking. Lim has founded his own startup, Cell Design Labs, to commercialize his engineering ideas. He declined to say how much money he has raised, but he says everyone working with T cells is stunned by the kind of money being thrown at the idea. “It’s a ‘wow’ type of situation,” he says.
The search to expand immune therapy now involves not only the world’s largest drug companies but also tech firms. Sharp says that last year Google held two summits at MIT of top immune oncologists and bioengineers to determine what parts of the problem could be “Googlified.” Attendees say the search giant paid special attention to new research techniques that fingerprint cells from a tumor biopsy in rapid-fire fashion. These methods might generate big data about what immune system cells are actually doing inside a tumor, and new clues about how to influence them. So far, Google’s life science unit, named Verily, hasn’t revealed its plans in cancer immunotherapy. But in New York’s Union Square, I met Jeffrey Hammerbacher, a former Facebook employee who now runs a lab that is part of Mount Sinai, the hospital and medical school. With 12 programmers in a light-soaked loft—the nearest thing to blood and guts is a photo of an exhausted surgeon on the wall—he’s also spending time on T cells. He’s developing software to interpret the DNA sequence in a patient’s cancer and predict from it how to goose the response of killer T cells.
A clinical trial by Mount Sinai should start this year. The patients receive a dose of abnormal protein fragments that Hammerbacher’s software predicts will train T cells to attack the cancer. “What was fun was that what we submitted to the [U.S. Food and Drug Administration] was not a molecule but an algorithm,” he says. “It might be one of the first times the output of a program is the therapy.”
In January, Juno Therapeutics (see “Biotech’s Coming Cancer Cure”) paid $125 million to acquire AbVitro, a Boston-area company that specializes in sequencing the DNA inside single T cells. Now Juno is trying to locate T cells that are active inside cancers and study their receptors. Juno’s chief scientist, Hyam Levitsky, says an experiment that used to take seven months now takes seven days. And data is piling up: an average experiment generates 100 gigabytes of information. “A lot of what is happening is technology-driven,” he says. “The questions have been there for a while, but there was no way to get at the answers. Now we’re visualizing them with new technology in ways we never could before.”
In March Pfizer appointed John Lin to head its San Francisco biotech unit, which develops cancer drugs and recently started making engineered T cells. He says the company had been negotiating with Cellectis well before the news of Layla’s treatment and that no one there was even aware the girl had been treated before it hit the news. “The publicity was a big surprise,” he says.
Lin says years of scientific work have finally resulted in a level of mastery that makes therapeutic products seem practical. He thinks the treatments will go beyond leukemia, and beyond cancer. “We think that this fundamental principle, engineering human cells, could have broad implications,” he says, “and the immune system will be the most convenient vehicle for it, because they can move and migrate and play such important roles.”
Researchers are already working on autoimmune disorders, like diabetes, multiple sclerosis, and lupus. Infectious disease is also in the sights of T-cell engineers. Edward Berger, a virologist at the National Institutes of Health who helped discover how HIV enters human cells, thinks it may be possible to permanently keep the virus in check, a so-called “functional cure.” In February, he says, he will start giving monkeys T cells genetically programmed to find and destroy any cell in which the simian version of HIV is replicating.
The actual process isn’t as simple as the theory. Berger is sure that years of missteps and do-overs lie ahead. Also, most protocols involving engineered T cells require patients, or monkeys, to take drugs that temporarily kill off their own T cells, which isn’t without risks. “Where the technology stands, it’s a pretty radical treatment,” Berger says. “You aren’t going to use it on a cold sore.” But despite all the progress that has been made treating HIV, a better approach is still needed. Because the virus hides in the body even after treatment, patients have to take antiretroviral drugs for life. With immune engineering, maybe not. Berger sees the chance of a one-time treatment that can hold the virus in check for good.
“I was totally inspired by the cancer work,” he says. “They cured leukemia, and we’ve borrowed it from them. The extension of those ideas for engineering the immune system against other things that ail people is a major front. I think HIV is the best candidate in infectious disease. If you talk to the HIV community, they are crying for a cure—a treatment that, ideally, you do once and never again.”