In Year of CAR-T Trouble, Can Bluebird, Penn Make Headway in Myeloma?

Xconomy Boston — 

Several drugs have been approved to treat multiple myeloma, a cancer of the bone marrow, in recent years. But it remains a nasty, persistent disease. Most everyone relapses.

Two rival groups, Bluebird Bio and researchers at the University of Pennsylvania, are presenting data in coming days to make a case that a cutting-edge therapy known as “CAR-T” treatment can become relapsed patients’ last line of defense—and perhaps more.

Both groups are reporting very early data, from Phase 1 trials, in a handful of patients. The peek Cambridge, MA-based Bluebird (NASDAQ: BLUE) is providing today seems to be superior to the early results from Penn, but there are strong caveats, too: Both groups are just beginning a long road of testing in patients, and CAR-T therapies for other blood-borne cancers have shown promising early results only to see their effects fade.

“My experience is that CAR-T therapies may last for several weeks, maybe even a month or six weeks before they slowly die down,” says Maung Myo Htut, a hematologist at City of Hope National Medical Center in Duarte, CA, who isn’t involved with Bluebird or Penn. “If we can prolong disease control by [at least] six months, I’d be very happy to use it.”

In multiple myeloma, the bone marrow’s plasma cells—a type of immune cell that normally churns out infection-fighting antibodies—grow rapidly and abnormally and crowd out healthy red and white blood cells. According to the American Cancer Society, about 30,000 people in the U.S. will be diagnosed with multiple myeloma this year. It’s the third most common blood cancer in the country after lymphoma and leukemia.

Most forms of CAR-T treatments use genetic engineering to turn a patient’s own immune cells into better cancer killers. Even if they can be tuned to wipe out multiple myeloma for several months for patients who have tried and failed several prior treatments, they must prove that the benefits last and are not outweighed by significant side effects. The CAR-T field is on edge after a major developer, Juno Therapeutics (NASDAQ: JUNO), reported last week more patient deaths in a high-profile trial of its most advanced therapy.

So what are the early returns for multiple myeloma? First up is Bluebird, which will present data tomorrow on its treatment, bb2121, at a conference in Germany. Bluebird reports that 11 patients have been treated, nine of them long enough as of Nov. 18 to measure the treatment’s efficacy. Seven of those nine have responded in varying degrees. Two patients have had a “stringent” complete response, which means no detectable plasma cells—the immune cells that turn cancerous in multiple myeloma—in the bone marrow four and six months after treatment, respectively. A third patient had a “very good partial response,” meaning more than a 90 percent drop in levels of a protein made by myeloma cells. The other four had “partial responses,” more than a 50 percent drop in the levels of that protein.

Bluebird chief medical officer David Davidson says the most significant side effects so far were “mild and well tolerated” cases of cytokine release syndrome, an immune reaction that can be life threatening. More specifics will emerge at tomorrow’s meeting. “It’s still early and we have to watch it play out,” says CEO Nick Leschly, “[but] we’re seeing quite a bit of efficacy without all the toxicity. And that’s the big win we were looking for.”

Side effects are a real concern. The patients who died in Juno’s trial succumbed to severe brain swelling. Other experimental CAR-T therapies have triggered severe, sometimes fatal cytokine release syndrome. But without significant safety problems so far, Bluebird officials say they can continue testing higher doses of bb2121, which so far have performed better (six out of six patients responded) than low doses (one out of three patients responded).

It took two and four months post-treatment, respectively, to get the two best responses, Davidson says. Will Bluebird see better, longer-lasting results as its doses climb? Or will higher doses over longer periods of time prove too dangerous?

“You have to wait it out, especially with this kind of trial, but [bb2121] looks very promising,” says Htut of City of Hope.

The Penn group, meanwhile, will report interim Phase 1 data from its treatment, CART-BCMA, next week at the American Society of Hematology’s yearly meeting in San Diego. The group published a preview in November that detailed six patients. One patient who had failed 11 prior therapies has an ongoing stringent complete response lasting more than seven months. A second patient had a very good partial response that held up for five months before the disease progressed. The other four have had little or no response.

What differentiates Bluebird’s treatment from Penn’s, at least at this early stage, are the side effects. In the Penn study, one patient suffered seizures and vision loss serious enough to prevent testing a higher dose. Penn also reported 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: 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: 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.