instances of severe cytokine release syndrome, anemia, and dangerously low levels of platelets, calcium, or phosphates, among other side effects. Still, Htut cautions that the patients Penn enrolled were sicker to begin with than those in Bluebird’s trial. Penn’s patients failed a median of nine lines of therapy, compared to a median of six for those in Bluebird’s study.
Penn’s trial is the second early attempt to test CAR-T in myeloma that has produced significant side effects. The first is an ongoing National Cancer Institute-sponsored study that was presented at ASH last year.
Penn plans to move forward with the study and enroll more patients, according to Susan Phillips, Penn Medicine’s senior vice president for public affairs. Penn hopes that with more data, its researchers can “better understand why some patients respond or develop severe side effects and others don’t,” she says.
Despite disbanding its gene and cell therapy unit in July, Swiss firm Novartis retains rights to the multiple myeloma work, according to spokesperson Dana Cooper. At the time of the shakeup, Novartis would only say it was pressing ahead with CAR-T therapies for acute lymphoblasic leukemia (ALL) and diffuse large B-cell lymphoma, with plans to file for regulatory approval next year if all goes well. Novartis is scheduled to report data on both at ASH. (Bluebird’s bb2121, meanwhile, is part of a partnership with Celgene.)
To be more efficient cancer killers, both the Penn and Bluebird CAR-T treatments are engineered to recognize a protein, B-cell maturation antigen (BCMA), on the surface of plasma cells. The modified cells are put back into the patient, where they hunt down and wipe out plasma cells with that signature. BCMA has “very exquisite expression on a plasma cell and nowhere else that matters,” which is why it makes a good target for a multiple myeloma CAR-T therapy, says Leschly.
The NCI-sponsored study provided the initial evidence, in humans, that CAR-T directed at BCMA could trigger meaningful responses in multiple myeloma patients. Though NCI researchers, Bluebird, and Penn are using CAR-T to attack the same target on plasma cells, each of the groups use slightly different tools and techniques to deliver their treatments, which may lead to different results. (French firm Cellectis (NASDAQ: [[ticker:CLLS]]) and partner Pfizer, and separately U.K.-based Autolus, are also developing BCMA-targeting CAR-T treatments for multiple myeloma, but neither are in human testing yet. Both will present preclinical data at ASH.)
Over the past few years, companies like Juno, Kite Pharma (NASDAQ: [[ticker:KITE]]), and Novartis have shown early, and in some cases stunning results for CAR-T therapies in certain blood cancers like ALL and acute myelogenous leukemia. That early success helped Juno and Kite go public in 2014 with sky-high valuations, raising money to fund a race through clinical testing.
Thanks to Juno’s setbacks, Kite could win that race to market with a CAR-T therapy next year if it doesn’t suffer any setbacks. (Kite hasn’t reported patient deaths, but some of its patients have suffered cases of cytokine release syndrome.)
But thorny questions remain about the safety and commercial viability of these treatments, which are sure to be expensive and are costly to produce. To lead to long-lasting remissions, CAR-T treatments have to help patients’ immune systems “remember” cancer and keep it at bay. Yet patient relapses have been a concern; durability past a few months has not been proven on a large scale.
While encouraged by Bluebird’s data, for example, Htut wants to see data on how patients’ modified T cells multiply over time. They have to “persist,” he says, to keep the cancer down without erroneously attacking the body and causing an autoimmune disease. “These are the safety issues that only time will tell,” he says.
Davidson says potential autoimmune problems are more of a “hypothetical concern.” A more realistic long-term safety issue might be low levels of the antibodies, immunoglobulins, produced by plasma cells, he says.
There are many treatment options available for myeloma—injectable antibody drugs, chemotherapies, pills, stem cell transplants, and more—and they’ve helped extend patients’ life expectancy dramatically from just a few decades ago. Yet there is no cure, and as Htut of City of Hope says, all patients progress at some point even if they initially respond to treatment. Cancer immunotherapy drugs known as checkpoint inhibitors, which have started to change how lung, skin, and other cancers are treated, haven’t had an impact on multiple myeloma on their own, though Htut points out that Merck’s pembrolizumab (Keytruda) has shown some promise in clinical studies when combined with other drugs.
“I think [checkpoint inhibitors] will have more and more of a role in the treatment of multiple myeloma down the line,” Htut says. “They’re not [ready for] primetime yet, but it seems like we’re heading in that direction.”
CAR-T may be heading in that direction as well, albeit with baby steps.
