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Spokane, Washington  Est. May 19, 1883

Seattle’s Juno Therapeutics ready for another round in war on cancer

By Martin Schlak Seattle Times

SEATTLE – When his second round of chemotherapy failed, physicians told Dan Symes that he had only a few more months to live. Symes, a 66-year-old former construction worker from Boston, had been diagnosed with an aggressive type of blood cancer the year before. By May 2016, he was so weak that he was unable to walk the few steps from his front door to his car.

Symes’ last hope was a therapy called CAR-T, a new kind of treatment that genetically modifies the body’s own immune cells to direct them against the hostile cancer cells. Because this treatment is not yet approved, Symes signed up for a clinical trial. Then he began to wait.

CAR-T cell therapy for aggressive B cell Non-Hodgkin lymphoma, the form of cancer Symes had, is the most promising product in the pipeline of Seattle-based biotech company Juno Therapeutics. Many oncologists expect CAR-T cell therapies to completely change the standard treatment for certain types of cancer in the next few years.

“In my career, there has never been a period I can think of in cancer where the prospects of new therapies have been so promising,” said Hans Bishop, Juno’s president and chief executive officer.

On eight floors, Juno combines laboratories and office spaces that previously were spread over three different buildings. About 350 Juno employees, both scientists and others, are now working under one roof in an open-office environment.

The move comes after some difficult times for the company. Last year, Juno reported that five patients in a clinical trial had died of a brain swelling after they had been given what was its most advanced drug in combination with others that were part of the treatment. The company ended that trial, and as a result lost the race for the first market approval of a CAR-T cell therapy. It was the Swiss pharma Novartis that three weeks ago received the green light from the Food and Drug Administration to roll out its therapy for a special type of leukemia.

Bishop said that while Juno won’t be the first in class, it is now set on becoming the best in class in terms of efficacy and tolerability of its drugs.

Whether Juno can live up to that promise will, to a critical degree, determine the company’s future.

Accepted in trial

It was a day in July 2016 when Symes received a call on his cellphone. He and his wife had gone out for some fresh air, Symes recalls in an interview over the phone. She was pushing him in a wheelchair while he was told he had been accepted for the clinical trial.

His wife started crying. He just said: “It is time.”

One month later, a sample of Symes’ blood was shipped from Massachusetts General Hospital in Boston to Juno’s manufacturing facility in Bothell.

CAR-T cells are a tailor-made, personalized medicine, which makes their production a challenge. Each batch of the drug is produced from the patient’s own blood. In different machines, T cells, a type of white blood cell that is able to fight a variety of pathogens, are filtered out, purified and genetically modified by inserting a string of DNA into their nuclei. The snippet of DNA reprograms the T cell and makes it produce a receptor on its surface that binds to a specific antigen of blood cancer cells called CD19, which eradicates them.

The engineered immune cells then are grown in a bioreactor, multiplying until a concentration of between 15 and 100 million cells is reached. Once the cells leave the incubator, they are kept frozen at 320 degrees below zero Fahrenheit, the temperature of liquid nitrogen, until they are ready to be delivered back to the patient.

The process takes up to 21 days and is only partly automated, making CAR-T an expensive therapy.

Bob Azelby, Juno’s chief commercial officer, said it’s too early to comment on the potential price of Juno’s now most advanced JCAR017 drug, the one Symes was getting. Novartis’ recently approved drug comes with a price tag of $475,000 per patient.

Despite the high price for such drugs, some experts doubt that CAR-T will ever be a commercial success unless it shows long-term durable remission in a high number of patients, something which is yet to be proved. Nonetheless, the expectations in the industry are high, reflected by the recent acquisition of Juno’s competitor Kite Pharma for $12 billion by the big pharma firm Gilead.

The history of the first company that commercialized a cell therapy – Seattle-based Dendreon – serves as a cautionary example, however. After the rollout of its prostate-cancer drug, Dendreon suffered from production costs that exceeded 50 percent of the treatment’s price. After more efficient and more cost-effective treatments won FDA approval, Dendreon eventually had to file for bankruptcy and was sold.

Bishop, who was Dendreon’s chief operating officer, said that Juno Therapeutics and Dendreon are not comparable: “They are very different companies in very different diseases with fundamentally different technologies.”

Juno aims at production costs that are much lower compared to the price of the drug, something it wants to achieve by speeding up the manufacturing process.

“I predict the amount of time it takes to make these products is going to go down rapidly,” Bishop said.

He believes new technologies will allow Juno to make the cells in three to five days, which would increase the turnaround of the facility.

Chris Ramsborg, Juno’s vice president of process and product sciences, said Juno’s manufacturing facility could produce thousands of batches per year, though he declined to be specific.

One of Juno’s early batches of JCAR017 arrived in Boston in September 2016. Symes had seen nurses preparing his hospital room for hours that day, bringing additional monitors and intravenous infusion sets. “They were setting the whole thing up for every possible contingency”, he said.

Then a doctor came in, took a syringe, and within 10 minutes, it was over.

From then on, a physician visited him almost every day to do neurological tests. The doctor would ask him to remember three words, ask questions about the weather or the date and eventually make Symes repeat the words. He still remembers them: “Milk, sensible, before.”

CAR-T cells can cause severe side effects. One of them is neurotoxicity, causing confusion or seizurelike symptoms, which is why patients in clinical trials are constantly tested. Another one, and the most frequent is cytokine-release syndrome, which can lead to dangerously high fevers and precipitous drops in blood pressure.

Stanley Riddell, an oncologist with the Fred Hutchinson Cancer Research Center in Seattle and a leading expert in the field of immunotherapy, said researchers are working on understanding those side effects and minimizing the risk by carefully controlling dosages of the CAR-T therapy.

With conventional chemotherapy and radiation, oncologists have aimed at the highest possible doses – an approach Riddell called “The bigger the hammer, the better.”

He added: “It’s the opposite in immunotherapy. You actually want to be much more precise about what you do.”

In contrast to many competitors, Juno uses a well-defined ratio of two specific types of T cells, which allows the company to operate with smaller doses, thereby potentially reducing the toxicities. As Riddell has a financial stake in Juno, he declined to comment on its clinical trials in detail.

The swelling of the brain that led to the death of five patients last year has so far not occurred again in Juno’s other CAR-T drugs. Juno plans to complete a detailed report on the fatalities later this year.

Riddell said that although the side effects of CAR-T have not yet been fully understood, it is not too early to move on to the market: “There is an unmet need. Patients are dying. We have therapies that are effective, we shouldn’t hold them back.”

He drew a comparison to the first chemotherapy drugs that were given to patients in the 1950s. “We didn’t really know how they worked. We knew they were toxic. … Now we have a much more sophisticated understanding of what exactly chemotherapy does to a cancer cell and to a normal cell. And I think that it is sort of the same thing with immunotherapy.”

Given further research, Riddell said, the side effects of CAR-T therapy will be manageable.

Positive results

The first results of the phase I study of Juno’s JCAR017 drug are promising and seem to meet Bishop’s best-in-class expectations. Three months after the treatment, half of the patients were in remission, meaning that all signs of cancer have disappeared.

In terms of efficacy, that puts Juno in the lead over its competitors Novartis and Kite Pharma.

“The JCAR017 data showed that we can get to similar levels of efficacy with just 50 million cells and have meaningfully lower incidences of severe toxicities,” Bishop said. Two thirds of the patients in the Juno trial did not experience any side effects at all.

However, the number of patients in the studies has been small so far – totaling about 50. Bishop said Juno is moving on to a bigger study that enrolls about 75 patients starting as early as this quarter. If successful, he expects to receive an approval for the market as early as the end of next year.

However, it is still a long way to make CAR-T a new pillar in cancer treatment. For now, it’s seen as a last-line therapy when all the other options have failed.

That’s the standard evolution, said Azelby, Juno’s chief commercial officer: “Any new drug that comes into oncology, you start in the later line and you have to beat the standard of care.”

He added: “The goal here is not just being used in the last line … but to move up the line.”

Taking into account the various types of blood cancers for which CAR-T therapies are approved or potentially approved, there are as much as 100,000 patients in the U.S. per year who could be eligible for CAR-T in the near future, Azelby said.

Oncologists hope that CAR-T therapy will one day also be able to target solid tumors such as breast cancer or ovarian cancer. Those still represent a major challenge for this type of treatment: Solid tumors express different antigens on their surface than blood cancers. They also have developed more complex strategies to escape immune recognition by T cells.

“There is a lot of hype and excitement, of course, because we are having some successes but … just think of how much we have to learn, and as we learn that how much more sophisticated we are going to get,” Riddell said.

For some patients however, CAR-T has already changed their lives.

Thirty days after Symes received a second infusion of Juno’s JCAR017 therapy, his oncologist called him in to show him two scans. One had been taken a few days before the first infusion, the other one was recent.

In the first one, his back was lit by cancerous cells as if a spotlight was shining on it. The second scan was dark. The malignant cells were gone.

Almost one year later, he has not regained his former strength and has to return to the hospital to receive drugs that suppress his immune system.

But he is alive.

Symes said he wants to enjoy the time that remains to the fullest. This January he bought a catamaran, and he and his wife are planning to do the Great Loop, a 5,600-mile sailing trip on the Great Lakes, the Mississippi River and along the Atlantic coast.

He knows that the cancer can relapse. Even with CAR-T potentially becoming one of the oncologists’ most powerful weapon, the war on cancer is far from being won.