The researchers and doctors at Seattle Children’s are embarking upon a complicated quest, involving multiple clinical studies of cutting-edge CAR-T cell therapies, to help kids and young adults with an aggressive form of leukemia. As of today, one key part of their plan can begin, thanks to a green light from the FDA.
New clinical studies are approved all the time, typically with little mention. But the field of CAR-T therapy, which puts live, genetically engineered T cells into patients to attack their cancer, merits more scrutiny. The nascent practice still feels like science fiction, even though the first two CAR-T products were recently approved and several others are in the biotech industry pipeline.
Seattle Children’s doctors can now treat pediatric leukemia patients with a type of CAR-T cell that attacks the cancer cells in two ways. Researchers in the U.K. have begun similar trials, but this is the first in the U.S. Targeting cancer two ways is a departure from the first wave of CAR-T therapies that have mainly have attacked a single target, a protein on the cancer cell surface called CD19.
That wave has produced the first two historic CAR-T approvals, including one for Novartis’s tisagenlecleucel (Kymriah) for the same pediatric cancer that Seattle Children’s wants to cure. (Gilead Sciences (NASDAQ: GILD) followed soon after with the first CAR-T approval for adults, to treat a type of non-Hodgkin lymphoma. Gilead acquired the CAR-T in its $11.9 billion purchase of Kite Pharma.)
But the Seattle Children’s study, which could treat as many as 33 kids and young adults, is part of a multi-trial scheme to explore several methods of fighting back against pediatric leukemia that anti-CD19 CAR-T alone couldn’t vanquish. Xconomy reported in September on the Seattle plans—and one girl whose cancer has stayed in remission following treatment.
Roughly half the young patients with leukemia who have received CD19 CAR-T cells from Seattle Children’s and Novartis (NYSE: NVS) see their leukemia return. (Across two major studies, 93 patients were in remission after one month; 55 remained in remission after 12 months.)
“We’re thrilled that PLAT-02 has gotten so many patients into remission,” says Seattle Children’s oncologist Rebecca Gardner (pictured), referring to the ongoing Seattle Children’s study using CD19 CAR-T cells alone. More than 100 kids and young adults have been treated. But a relapse after CAR-T treatment is grim, indeed, leaving doctors with no other treatments to deploy. “We want them to get into remission and stay in remission,” says Gardner, who is charge of the clinical side of the program.
As part of their plan to prevent relapses, Seattle Children’s researchers want to find out if a different tumor target, CD22, can be an Achilles’ heel of tumors that bounce back after a CD19-directed attack. In about a quarter of all patients treated with CD19-directed T cells, the cancer mutates and comes back without CD19, leaving them invisible to the T cells.
For the new trial, dubbed PLAT-05, Gardner and colleagues will engineer each patient’s T cells to create a “mixed population” that is pumped back into his or her bloodstream. Some cells will go after CD19, some will go after CD22, and some will go after both. The mix could sustain the attack even if one type of cell is rejected by the patient’s immune system, says Gardner. But she acknowledges that other researchers are working on different technical approaches. “We’ll know in a few years if one strategy is better than another,” she says.
Gardner and colleagues are testing other next-generation CAR-T concepts, as well. In a trial dubbed PLAT-03, they are giving relapsed patients a fresh batch of CD19-directed CAR-T cells and adding something radically new: more of the patient’s T cells, engineered to mimic CD19-carrying cancer cells and act as a vaccine to encourage a longer-lasting immune attack. (Because it is the first-ever human test of this approach, the FDA wants the first participants in the trial to be over 18, says Gardner. None have yet emerged.)
In a trial called PLAT-04, participants whose leukemia has relapsed and no longer carries CD19 are being treated with CAR-T cells that only attack CD22.
In total, the series of PLAT trials is designed to give the Seattle Children’s researchers a road map for turning CAR-T into a therapy that can be used as more than just a last-ditch treatment, as it is now. Perhaps within two years, they’ll have enough insight from the series of small trials to begin something larger—call it PLAT-06. Ultimately, says Gardner, patients might start with CAR-T that attacks CD19 and CD22 and receive the T cell vaccine boost.
There are significant hurdles. Seattle Children’s has funding for the new PLAT trials, but if success points to a PLAT-06 study, it’s not clear who would fund it. And with Novartis’s tisagenlecleucel approval in late August, the bar to approve a new therapy for pediatric ALL is now set higher. Novartis set a price of $475,000, although it promises not to charge for patients who don’t respond to the therapy within a month.
Notably missing from the short CAR-T approval list is the program Seattle Children’s has developed. A couple years ago, it was clear that Novartis was progressing faster, which made the Children’s researchers shoot for their more audacious goal. But by doing so, it made a fast approval nearly impossible for its corporate partner, Juno Therapeutics (NASDAQ: JUNO). Juno has shown no interest in going head-to-head with Novartis in children’s leukemia.
Photo courtesy Seattle Children’s.