Gene-modification is the next frontier in the fight against cancer
In 2010, Bruce Levine and Carl June, two immunologists at the University of Pennsylvania, were awaiting the results of their newly-invented cancer treatment. It was being trialled on three patients with untreatable lymphoid leukemia. Called CAR-T cell therapy, the treatment worked by extracting immune T-cells from the patient, genetically modifying them in the lab to make them target cancer cells, then infusing them back into the patient to run their course. When the results came in, they revealed that the single dose of infusion therapy had eradicated the leukemia in two patients, destroying kilograms of cancer cells. The third patient had a partial response to the therapy but later died. But the other two remained disease-free. By that point Levine and June had been developing CAR-T cell therapy for over a decade, and had endured constant scepticism from fellow scientists: “In those early years, what we were doing was looked on as something quaint, or boutique,” recalls Levine, who works at the Perelman School of Medicine at the University of Pennsylvania and will be amongst the speakers at the WIRED Health conference in London on March 13. Without the funds to test the therapy on other patients, they made the bold decision to publish with what they had – and in 2011 their study “exploded” onto the scene, says Levine. “Things changed rapidly, and dramatically.” Fast forward to 2017, when the United States Food and Drug Administration (FDA) made the landmark decision to approve two ‘drugs’ that use CAR-T cell therapy – the injection of engineered immune cells into patients – to treat blood cancers. First, in August 2017 it approved Kymriah, a treatment developed by drug company Novartis for acute lymphoblastic leukemia (ALL) in children and young adults. Then in October 2017 it licensed Yescarta, a Gilead Sciences drug for adult diffuse large B-cell lymphoma. These made history as the first-ever gene therapies approved by the FDA. “It was a career highlight for all of us, but more importantly the patients,” Levine says. The FDA’s decision heralds a new era of personalised cancer treatment. By using the patient’s own cells, CAR-T cell therapy makes it unlikely that tissue will be rejected. Additionally, the one-off infusion gets around the problem of multiple treatment rounds that characterise other cancer drugs, like chemotherapy. There are fewer side effects, and researchers have also proved its longevity: results from a clinical trial of Kymriah released in February show that 76 per cent of the cancer patients survived for a year or more, something unheard of with other treatments. Because they precisely target malignant cells, CAR-T cells have “unparalleled effectiveness in treating blood cancers where other therapies have failed,” says Levine.The therapy stems, in part, from Levine’s early work on HIV. In 1992 while doing a PhD in immunology and infectious diseases, he came across Carl June’s research on T-cell signalling: at the time June was becoming a pioneer in the field of synthetic biology. Levine went to work in June’s lab at the Naval Medical Research Institute in Bethesda, where he took on a project to grow healthy immune cells in the lab, and put them into the bodies of patients with HIV. After proving that this technique could boost patients’ immune function, Levine and June realised that it could be tailored to treat cancer as well.The challenge of cancer is that it has evolved to evade the immune system, either by suppressing its defences, or by cloaking itself to avoid identification. To get around this problem, Levine and June began collaborating with a company called Cell Genesys: they started engineering T-cells to contain genes that would make them express specific receptors that targeted malignant tissue. These receptors – named Chimeric Antigen Receptors (CARs) after the hybrid creatures of Greek mythology – could be made to target CD19, an antigen typically present on the cells of blood cancers like leukemia and lymphoma. “You realise you can redirect immune cell specificity in this way,” says Levine. “In a sense we’ve trained that T-cell to see something it would not ordinarily see.” Multiplied in the lab and then let loose inside the body, these engineered CAR T-cells can rapidly locate, bind to, and destroy the malignant cells. So far, blood cancers have been the primary target because of the obvious moral imperative to treat diseases like ALL, which affect children, says Levine. But there are practical motivations, too. The CD19 antigen in these blood cancers creates a clear bullseye for the T-cells. In other cancers, those targets aren’t always so sharp. Either the cancer cell antigens express in healthy tissues as well, making it too dangerous to launch an attack, or in the case of solid tumours, they’re shrouded in a matrix that’s difficult for T-cells to permeate. Solving these problems is now the new frontier for CAR-T cell therapy.Levine predicts that the next FDA approvals will be for myeloma, a bone marrow cancer for which therapy development is currently underway. Next up will be tumour-based cancers. “A number of groups, including ours, are working on targets in solid cancers,” – including pancreatic, ovarian, breast, and prostate, he says. The blood cancer treatments also need to be refined: of the patients who survive for a year or more, up to half are still going into remission during that time. Levine and colleagues are now trying to identify other targetable antigens, to expand the scope of T-cell attack.But the biggest future challenge will be to bring down the cost of CAR-T cell therapy, says Levine. Kymriah and Yescarta cost $475,000 and $373,000 respectively for one infusion. “They’re bespoke therapies; they’re generated from and for each patient. So it’s not something you can scale up from a one-litre bioreactor to a five-thousand bioreactor, and then you’re done,” Levine explains. And yet to reach more people, it undoubtedly needs to get cheaper. Levine thinks that as more gene therapies are developed, it should drive a revolution in the way we manufacture these drugs. “The engineering challenge is to take our very nano production process and automate so that we’re able to treat more patients – particularly when we get into the diseases that affect more people, such as lymphoma and myeloma, and certainly solid cancers,” he says.Levine is now working with a number of research centres to speed up that manufacturing process. Like all big ideas, this will take time to become a reality, he says. But that hasn’t stopped him.Bruce Levine will be speaking at WIRED Health 2018 on March 13 at The Francis Crick Institute in London. To find out more, and to book tickets, click here.Updated 22.02.2018: The article has been edited to reflect the fact that one patient partly responded to the therapy before dying. Previously it stated that the patient went into remission before dying.