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

Xconomy National — 

It’s a struggle that comic-book fans know well. Ordinary people, bestowed with super powers from a spider bite or gamma rays, struggle to harness their own abilities.

T cells, key soldiers of the immune system, are wrestling with new-found super powers, too. Certain T cells hunt down invasive viruses, bacteria, and the body’s own bad seeds—the early signs of cancer. But cancer has ways of evading the immune system, so researchers are engineering T cells to give them extra cancer-fighting talents. These so-called CAR-T treatments, administered experimentally in clinical trials, have helped dozens of patients with otherwise untreatable blood cancers.

Now the field’s first-ever regulatory approval is looking like a strong possibility, making this a watershed year for CAR-T therapy. But the supercharged T cells remain an enigma. Experts are wrestling with the super-hero problem that threatens to limit their usefulness: How can the cells be engineered to kill cancer without running amok?

“It’s more important than anything else to keep learning how CAR-T cells work and how they potentially carry risk,” says Amir Fathi, an assistant professor of medicine at Harvard Medical School. As director of the leukemia program at Massachusetts General Hospital in Boston, Fathi treats patients with experimental CAR-T therapies.

(CAR-T stands for chimeric antigen receptor T cells, which describes the modification that picks up the signals of tumor cells—sensitive T cell spyware, if you will.)

With Kite Pharma (NASDAQ: KITE) of Santa Monica, CA, nearly ready to ask the FDA to review its CAR-T axicabtagene ciloleucel as a treatment for adults with non-Hodgkin lymphoma (NHL), the field’s first-ever approval could be months away. International drug giant Novartis (NYSE: NOV) might not be far behind, with a CAR-T for pediatric patients with acute lymphoblastic leukemia (ALL).

For now, the Kite and Novartis products are meant for narrow groups of patients who have failed to improve with other therapies, including chemotherapy and bone-marrow transplant. Their doctors are thrilled to have the first generation CAR-Ts. “The patients whom these trials are targeting, they’re typically highly refractory, they have no options left,” says Krishna Komanduri, director of the Sylvester Comprehensive Cancer Center Adult Stem Cell Transplant Program at the University of Miami.

But is a last-ditch lifeline for patients with severe cases of two blood cancers the ceiling for CAR-T? Doctors, patients, and investors who have poured billions of dollars into the field have much higher hopes that the living cells will stand alone as long-term treatments, even cures, not just improvements upon current standards or temporary bridges to get patients healthy enough for bone-marrow transplants—which are fraught with risks, too.

The risk of dying from transplants has come down under 20 percent in recent years, which is still higher than the overall death risk from CAR-T. But transplants are proven to cure cancer; CAR-T therapy has a long way to go. “I think we need to see no evidence of disease [in patients] for several years, ideally three to five, before even comparing it to transplant,” says Vinay Prasad, a blood cancer specialist at Oregon Health & Science University in Portland, and a critic of what he sees as a rush to use—and pay for—expensive new medicines and procedures.

Ambitions also include eventual treatment of more common solid tumors—breast, colon, and lung, for example. But the obstacles in realizing those ambitions—understanding CAR-T’s potentially deadly side effects, training a wide range of medical staff, and convincing healthcare insurers that the treatments are worth paying for—will not be easy to surmount.
As Komanduri notes, bone marrow transplants from donors have been known for decades to cure lymphoma, but inadequate Medicare coverage has held the field back. “The endgame should not be proving that a technology works in the clinical trial setting and securing FDA approval,” says Komanduri, “but ensuring we have a framework that maximizes access to curative treatments in a sustainable way.”


As noted in Xconomy’s searchable CAR-T clinical results database, many programs have had stunning early results. More than 80 percent of leukemia patients, for example, have shown no signs of cancer a few weeks after treatment. Relapse rates climb after a few months in most studies. Lymphoma patients have had lower rates of remission, but in the Kite Pharma program that could be up for approval this year, the rates have stayed stable for six months—a big deal in the CAR-T world.

Significant side effects are likely to limit CAR-T therapy to major treatment centers that can handle their unpredictability and sudden severity. Doctors working on CAR-T studies say they’re getting a handle on one common side effect, called cytokine release syndrome, with steroids and other drugs. But CAR-T treatments are also causing 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 to infection. It remains to be seen how much risk the immunosuppression will add to the procedure.

So far, Cellectis and its partners have reported manageable immune reactions in the two infants and the first four people from two UCART19 European trials that began last year. Some of them were transient skin rashes, according to information presented to the NIH advisory committee in December.

More data should arrive this year or in early 2018. Pfizer is expanding the Phase 1 UCART19 program to the U.S., and Cellectis is starting a Phase 1 U.S. study of a different CAR-T, UCART123, to treat acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm, an often misdiagnosed blood cancer.

If it works, allogeneic CAR-T will almost certainly be cheaper than autologous. One donor could supply enough blood to provide up to 4,000 doses, says Choulika. Choulika says one vial of UCART123 cells necessary for a treatment at this stage costs $4,000, and with behind-the-scenes improvements, the price should keep coming down. (The cells themselves will be only one part of the overall eventual cost, of course—and it’s too early to make predictions.)

Various estimates peg autologous production in the tens of thousands of dollars per patient. Autologous developers feel the pressure to be faster and cut costs. In Juno’s manufacturing site near Seattle, employees point out a contraption, a bit bigger than a vintage Japanese pachinko machine, that’s meant to do the work currently spread across many machines and rooms.

It’s a prototype called “the excellence machine,” either a spasm of self-improvement jargon or an impish nod to Bill and Ted of teen movie fame. It’s at least a few years away, says CFO Harr, but could be a “radically” different way of manufacturing cells. In the interim, Juno needs to speed things up, like the safety checks on a cell product before it’s released to the patient. “You have to automate quality,” says Harr. “It’s still more manual than we’d like.”

Usman “Oz” Azam, who is developing T cell medicines as CEO of Tmunity Therapeutics in Philadelphia, says that “bringing down the cost of goods” is a “big battle in the space right now.”

“I was heavily involved in that in my former role,” says Azam, who until last year ran Novartis’s cell and gene therapy group. (It was disbanded last year, with 120 jobs cut, but Novartis pledged to continue development of its lead experimental CAR-T products.)

For autologous CAR-T, analysts have floated possible prices in the hundreds of thousands of dollars, the same range as the most expensive rare disease treatments. In late 2015, a British academic group mocked up theoretical U.K. pricing models. CAR-T used as a bridge to prepare patients for a bone-marrow transplant was considered less valuable than CAR-T that could stand alone as a potential cure. (With many caveats, the group estimated rough costs of each north of a half-million dollars per patient.)

Others in the field are watching. Bristol-Myers Squibb (NYSE: BMY), one leader in another kind of cancer immunotherapy, hasn’t taken a shine to CAR-T. Allogeneic success could change that, its top deal maker told Xconomy recently. “We would love to see a technology like that be more ‘off the shelf,’ because I think it fits our business model well,” said Paul Biondi, Bristol’s senior vice president in charge of business development. “Also I think you’ll see the opportunity for [CAR-T] to expand beyond just a limited numbers of hematologic tumors.”


CAR-T has made progress against leukemia and lymphomas because, in part, the collateral damage is manageable. Those cancers carry a protein called CD19 that CAR-T cells are programmed to recognize. But they also attack healthy immune “B” cells that also carry CD19; fortunately people can live without their B cells with anemia treatments. There are other reasons CD19 is “in many ways the perfect target,” says Stanley Riddell, a top T cell researcher at the Fred Hutchinson Cancer Research Center in Seattle. (He is a Juno co-founder and holds a stake in the company.) “It’s highly expressed on the tumor, and there’s a lot of tumor [so] the CAR-T cells get very activated.”

This year, we should see what happens when CAR-T programs go after less-than-perfect targets. The first treatments for multiple myeloma, the third most common blood cancer in the country after lymphoma and leukemia, have reached the clinic and more are coming.

But the biggest step for CAR-T therapy would be success in solid tumors, such as lung, breast, and colon cancers, which are far more prevalent than blood-borne cancers. “It’s the holy grail we’re looking for,” says Aya Jakobovits, the former president and CEO of Kite Pharma who now runs Adicet Bio, a developer of allogeneic cell therapies.

Several early studies in solid tumors, such as this one and this one, could provide data this year—the first real peeks at the challenges CAR-T faces in making the leap.

Solid tumors have built more ornate defenses into their immediate environment, which makes them less penetrable to a CAR-T assault. They tend to have proteins that are also on healthy tissue, but unlike B cells that are wiped out by anti-CD19 treatments, it’s not tissue that patients can typically spare. Researchers have to choose their targets carefully. “We don’t expect first results in solid tumors as spectacular as in blood cancers,” Juno CEO Bishop said in January.

Jakobovits strikes a different tone: “If you use the right cells with the right properties we should aspire to get similar responses as in hematological cancers.”


Administering CAR-T therapy isn’t like dispensing pills or infusing chemotherapy. Treating patients with CAR-T “requires an immense amount of planning and coordination and meetings,” says Fathi of Massachusetts General Hospital. He ticks off a long list of personnel who have to be in the loop, including cell processing experts, nurses, clinical trial coordinators, lab researchers, pharmacists, and physicians who specialize in infectious disease, pulmonary and critical care, and neurology.

While oncologists interviewed for this article believe the learning curve from one CAR-T to the next should be less steep over time, they also questioned whether the therapy will ever be straightforward enough to administer outside of major cancer centers, especially those that have experience with bone-marrow transplants.

“I don’t think it’ll be widely distributed through community for oncologists to use,” says Solomon of the Blood & Marrow Transplant Group of Georgia. “And that’s OK. The model of transplant is similar. We don’t allow just any center to do transplants.” Solomon and others would like to see the same group that sanctions transplant centers expand its purview to CAR-T therapies.

But as the Hutch’s Riddell notes, patients with solid tumors could have different responses to CAR-T than patients with blood cancers. That would make the learning curve for medical staff steeper than expected.

Meanwhile Kite says it is lining up more than 70 transplant centers, which treat nearly 90 percent of patients with the most common form of NHL, to be ready when FDA approval comes. Down the road, Kite CEO Belldegrun says he wants to move into community centers and treat patients who aren’t “the sickest of the sickest,” like those with slow-growing indolent NHL. He’s confident everyone will learn what’s necessary. A pooling of analyst estimates tabbed axicabtagene sales at $1.7 billion in 2022, according to Evaluate Pharma. (It should be noted that drug-sales projections several years ahead are far from a sure thing.)

But will insurers pay for CAR-T? Cell therapy companies will argue for the high value of putting sick people’s cancer into remission, but it’s complicated. For example, what if the CAR-T therapy extends a person’s life and makes them eligible for an expensive stem cell transplant? Kite, it should be noted, has not said how many of the 36 people whose lymphoma has disappeared in the Zuma-1 trial have subsequently undergone transplants.

What if some patients go through the cell extraction and manufacturing process only to find their modified cells aren’t having any effect? To decrease those chances, companies and academic researchers would love to find biological signals that flag when a person is more or less likely to respond to treatment—or is likely to suffer terrible side effects. But similar efforts at precision medicine in other forms of cancer immunotherapy have been slow to materialize, and aren’t likely to do so in CAR-T without much deeper data sets.

When asked if pay-for-performance schemes would make sense with CAR-T, Juno CEO Bishop says the concepts are interesting but for now face too many impediments, such as Medicare rules.

Kite CEO Belldegrun declines to discuss specifics around pricing, except to say that Kite is talking to insurers and their agents. Meanwhile, President Donald Trump is promising lower drug prices through sound bites, the pharma lobby and insurers’ agents are firing salvos at each other, and insurers are playing hardball on first-ever treatments for rare diseases. When asked about the current climate, Belldegrun seems unfazed. “It’s hard to believe that people won’t realize this is a true revolution and you can melt cancer away in a month,” he says. “If that’s not worth paying for, what’s worth paying for?”

T cell image by the National Institute of Allergy and Infectious Disease via a Creative Commons 2.0 license.