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Biotech firms tests cell therapy for cancer

Patients’ modified immune cells used in clinical trial

By Martin Schlak, The Seattle Times
Published: September 25, 2017, 12:00pm

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.”

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