When five patients with a difficult type of leukemia died last year in a clinical trial run by Juno Therapeutics, it was a big setback for the Seattle biotech and its plans for cutting-edge CAR-T cancer therapy. A year later, Juno is finally explaining what happened and promising to return with a new product.
The report, presented today at the Society for Immunotherapy of Cancer conference near Washington, DC, explains why the study participants, all with advanced acute lymphoblastic leukemia (ALL) that had resisted other treatments, succumbed unexpectedly to severe brain swelling, known as cerebral edema.
The report also sheds some light on Juno’s (NASDAQ: [[ticker:JUNO]]) decision last July to restart the study, dubbed ROCKET, after the first three deaths. A few months later, two more participants died and the study was shut down for good. The CAR-T product involved was shelved earlier this year.
CAR-T therapy has shown great promise, knocking out otherwise untreatable cancer, at least temporarily, in dozens of adults and kids with certain types of leukemia and lymphoma. The most promising form of CAR-T uses a patient’s own T cells, drawn from a blood sample, genetically modified outside the body, then re-introduced to the patient.
But it also has severe side effects. In some cases, like an overheated immune reaction called cytokine release syndrome (CRS), doctors are learning how to anticipate and control the worst symptoms.
CAR-T related cerebral edema, however, is more perplexing. There have been cases in other CAR-T studies, but nothing like the deadly cluster in Juno’s trial.
“It’s great they’re getting out in public with this,” says Stefan Grupp, head of cancer immunotherapy at Children’s Hospital of Philadelphia who treated the first pediatric patient ever with CAR-T.
With the deaths in the ROCKET study, Grupp says, the specter of CAR-T-related cerebral edema “went suddenly from ‘on no one’s radar screen’ to ‘major problem.’ It was really unexpected.”
Grupp is unaffiliated with Juno. His pioneering CAR-T work has been with CTL-019, a therapy that began at the University of Pennsylvania’s medical school, where he is a professor. In the hands of Novartis, it became the first CAR-T ever approved under the name tisagenlecleucel (Kymriah).
Juno officials have speculated for months that several factors contributed to the ROCKET deaths. Grupp says the study adds solid data to the theories, and one in particular: that the genetically modified cells, once pumped back into the patient, start to multiply too fast. “Everyone had this guess without data to support it that the speed of cell proliferation was an important factor,” Grupp says. “Their analysis shows that’s probably correct.”
The problem of cell proliferation is also present with CRS. When a patient has a lot of cancerous cells—a high tumor burden—the modified CAR-T cells rapidly multiply and attack, like sharks in a feeding frenzy, but also release a flood of
