Possible Cures. Mystery Deaths. Daunting Costs. Can CAR-T Be Tamed?

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neurological problems — seizures, confusion, and loss of balance, memory, even vision—that are less understood. “Those events can last days to weeks, and they’re scary,” says Scott Solomon, an oncologist at the Blood & Marrow Transplant Group of Georgia in Atlanta. Most patients recover, says Solomon, but “we have less understanding of the pathophysiology, why it happens, and what the optimal management is. We also can’t predict who will have it.”

There is no more glaring example than what happened to Seattle-based Juno Therapeutics (NASDAQ: JUNO), one of the early movers in the CAR-T field. Five of 38 adults with ALL in a key trial called Rocket died last year of severe brain swelling, a side effect that no other CAR-T program had reported in such a cluster or with such dire circumstances. In January, CEO Hans Bishop told Xconomy Juno was investigating “every manufacturing and product attribute you could think about, and at a whole series of clinical attributes related to patients and their pretreatments.”

On March 1, Juno announced “multiple factors” could have contributed to the Rocket deaths. For example, officials highlighted the danger when the modified cell population, once put back into the patient, expands too fast—perhaps based on a patient’s age, perhaps in response to a high level of cancer cells. But executives on a conference call did not say why the cells caused the unusual and deadly brain swelling.

The FDA has begun collecting CAR-T safety data in a pilot project, but the lack of clarity on safety remains frustrating,  says Stanford University pediatrician and bioethics expert Mildred Cho, a member of a National Institutes of Health advisory committee that reviews potential gene and cell therapy trials. The committee “has much deeper expertise in all the areas relevant to CAR-T” than the FDA but cannot assess safety because drug owners are basically on an honor system to link deaths to their drugs. “Obviously, there is little incentive to link interventions to bad outcomes, especially where there are financial incentives to do the opposite,” says Cho.

Juno officials first reported three deaths in July. The FDA put the Rocket study on hold for a few days then allowed it to resume. Juno announced two more deaths in November. Officials said on March 1 they hoped to publish investigation results in the future. The company’s setback left a clear path for Kite to be first to market, with Novartis close behind.

Meanwhile, Juno’s new top candidate, JCAR017, has different engineered parts than JCAR015 (more about these differences in a moment). It says an ongoing Phase 1 study in NHL will lead to a larger trial this year, which in turn would be a stepping stone to approval, perhaps in 2018. Juno reported in December that out of 20 patients whose response could be measured, 12 had complete remissions, or no trace of cancer. Three of 22 patients had serious neurological side effects and one had CRS. Bishop said in January that to “change the standard of care” in NHL, Juno would like to see JCAR017 produce complete remissions that last six to nine months in 30 to 40 percent of the patients who receive it.

Many of the differences between JCAR015 and JCAR017 are indicative of adaptations the entire field is making to exert multiple levels of control over T cell products. For example, JCAR017 is made of a precise ratio of two T cell types; one is an active killer and the other is more a helper in the overall immune response. JCAR015 was an undifferentiated mix. The goal is to put “a more comparable product in every patient,” get the dose right, and “ultimately get a more predictable response,” says Juno CFO Steve Harr.

Just as CAR-T’s frightening side effects can be unpredictable, so are the occasional treatments that do nothing. Several groups are working on modifications that would let doctors either dial up the augmented cells’ activity if they’re not working well enough, or shut them down if they start causing too much collateral damage. Bellicum Pharmaceuticals (NASDAQ: BLCM) of Houston wants to test its controllable T cells in patients with pancreatic cancer. And Kite has invested in a spinout from the University of California, San Francisco, to build control switches into future CAR-T products. But how much control it’s possible to exert remains to seen. As Juno’s Harr notes, T cells are “living breathing things that will always have more variability once they get in the body.”


The programs generating the big headlines so far use autologous CAR-T—treatments that use a patient’s own cells. But what if T cells can be drawn from the blood of any donor, then engineered and administered to patients, requiring less complicated manufacturing and logistics?

The first data from these “off the shelf” CAR-T cells are beginning to trickle in. The most notable aren’t clinical data. UCART19 from French developer Cellectis (NASDAQ: CLLS) put the ALL of two British children into remission after their parents requested compassionate use to treat their desperate cases in 2015. They were not part of a trial.

But studies are underway that by year’s end might offer clues about the competitiveness of off-the-shelf, or allogeneic, cells with autologous programs—perhaps at a much lower cost, as its proponents argue. While Novartis (working with the University of Pennsylvania), Celgene (a huge partnership with Juno and a smaller one with Bluebird Bio), and Amgen (with Kite) have pursued autologous CAR-T, Pfizer (NYSE: PFE) has thrown in with Cellectis, using deals to take a 10 percent stake in the company and get partial control of Cellectis’s UCART19 product. “We wanted to look for the next big leap in the field,” says Pfizer vice president of CAR-T research Barbra Sasu. “We saw that to be the allogeneic approach.”

Sasu cites many reasons for the choice; one in particular resonates in the wake of the Juno deaths. “In autologous [CAR-T], every patient is a different experiment,” says Sasu. But allogeneic products have fewer variables, she says, and should make clinical investigation clearer. “You should understand the setbacks better,” says Sasu.

With allogeneic treatments, there is fear of a catastrophic immune clash between the foreign cells and the patient. To avoid deadly reactions, Cellectis is wiping out patients’ native T cells with a drug called alemtuzumab. (The Cellectis cells are genetically edited to be alemtuzumab-resistant.) With no native T cells, patients are highly susceptible … Next Page »

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