last December, scientists at Juno Therapeutics reported at the American Society of Hematology (ASH) meeting that, in an ongoing Phase 1 trial, its chimeric antigen receptor (CAR) T-cell therapy, JCAR015, put 24 of 27 adults with refractive acute lymphoblastic leukemia (ALL) into remission, with six patients remaining disease free for more than a year (ASH 2014, Abstract 382, 2014). This disease is extremely hard to treat and progresses rapidly when it becomes refractory; most patients die within a few months. “This response rate is unprecedented for patients who had stopped responding to all other treatments,” says Michel Sadelain, a founding director of Memorial Sloan Kettering’s Center for Cell Engineering and a cofounder of Juno.
Founded just a year earlier, the Seattle-based company now has four CD19-targeting CAR T-cell therapies in trials. The premise is simple: extract a patient’s T cells from blood and train them to recognize and kill cancer by modifying them with a viral vector to express an artificial, or chimeric, receptor specific for a particular cancer-associated antigen—in this case, CD19, an antigen expressed in B-cell–related blood cancers—then reinfuse the cells back into the patient. (See illustration at left.) The engineered cells recognize and kill cancerous cells, while reactivating other immune players that have been dampened by cancer’s inhibitory signals. “CAR therapy is at the same time cell therapy, gene therapy, and immunotherapy,” says Sadelain. “It represents a radical departure from all forms of medicine in existence until now.” Promising preclinical results have moved Juno’s CD19 therapies into trials for ALL, non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia (CLL), and the company has three more CAR T-cell immunotherapies for a number of solid cancers close behind.
A few weeks after the ASH meeting, Juno went public for a whopping $264.6 million, the largest biotech initial public offering (IPO) of 2014. Within a month, the company’s valuation rose from $2 billion to $4.7 billion, the largest among biotechs in a decade. By the end of 2016, the company plans to have 10 drug trials for six diseases up and running using CAR T cells produced in a brand-new manufacturing facility.
And Juno is not alone. This relatively new sector is experiencing a frenzy of scientific activity, corporate partnering, and financing that took off in late 2013, continued throughout 2014, and moved straight into the new year with no sign of letting up. By now, most major pharmaceutical companies have jumped into the CAR T-cell arena. In the past two years alone, at least half a dozen companies have made deals worth hundreds of millions of dollars up front, with much more expected in the future as products move through the pipeline. (See chart below.) This influx of funding is now supporting dozens of clinical trials.
While most of these studies are currently aimed at late-stage disease for which other therapeutic options have failed, researchers in the field anticipate that these immunotherapies could replace standard cancer treatments in the future. “While we are evaluating these therapies in advanced cancer now, we absolutely believe that they have the potential to become frontline therapies,” Sadelain says.
Long time coming
CAR T-cell therapy has had a lengthy run-up to what may appear to be overnight success. The first CAR T cells were developed at the Weizmann Institute of Science in Israel in the late 1980s by chemist and immunologist Zelig Eshhar. In 1990, Eshhar took a year-long sabbatical to join Steven Rosenberg at the National Institutes of Health, where they prepared CARs that targeted human melanoma. “We designed CAR T cells to overcome a number of problems in getting T cells to attack cancer,” says Eshhar. These problems included a tumor’s ability to escape immune recognition by silencing the major histocompatibility complex molecules and the generally immunosuppressive tumor microenvironment…..
