Hurdles abound in race to bring customized cancer treatments to masses

The idea is tantalizing: Reengineering patient’s own immune cells to attack the cancer that is killing. Scientists have shown it can be done, cure patients of cancer of the blood of another terminal mode.

But faith in this approach, called CAR-T immunotherapy, has been shaken in recent months.

First, Juno Therapeutics, a leading company in the field, announced that four patients in their clinical trials had died. Then, this week, Novartis – one of the main contenders in the race for the marketing of the CAR-T therapy – closed its unit cell and gene therapy and announced plans to lay off 120 employees. The company says it is still working on CAR-T, but the move struck many analysts as a shelter.

Meanwhile, companies competing to bring CAR-T for the market are up against enormous challenges in their attempt to expand the highly personalized treatments and convert oncology blockbusters. They are also running into problems using CAR-T for the treatment of solid tumors, unlike blood cancers, which limits the potential market. Then there are Serious side effects associated with the experimental treatment, which can send patients into a coma and cause your brain to swell.

A analyst BTIG wrote this week that has become “generally skeptical” about the market potential for Juno and the kite, since blood cancers are a golf niche full of potential therapies CAR-T.

to be sure, there still excitation in the field. This week, Amgen bought the global development and commercial rights for T cell therapy Boehringer Ingelheim that targets multiple myeloma. But it is more tenuous.

“I think the story line today is, CAR-T is really walking a fine line,” said Brad Loncar, founder of a fund for cancer immunotherapy. “A year ago, there was certainly exuberance. But now, we are on the precipice of people pulling back.”

Mass production of a personalized therapy

making a CAR-T product is complicated. It is the collection of the own patient’s immune cells, reengineering of them so they have the ability to find and kill a cancer cell, then feeding these redesigned again in the patient’s body T cells.

“therapy CAR-T is a highly individualized product, even though the process that every patient goes through is very similar,” said Dr. Stephanie Goff, a surgeon at the National Cancer Institute who is working with the kite in their treatments.

Enlargement is a difficult prospect for CAR-T therapy. The increase in capacity for the manufacture of a biological medicinal standard could involve encounters the size of a bioreactor so it can pump out, for example, 5,000 liters said Bruce Levine, professor of gene therapy at the University of Pennsylvania who has worked with Juno Therapeutics.

But the CAR-T therapy is so highly personalized that manufacturers must effectively build 5,000 liter bioreactors -. And then train enough staff to operate many complex machines

“I think we are going to take years, though certainly not decades, to reach the point where we almost complete automation,” Levine said.

to avoid that obstacle, a company – the Cellectis biotechnology, which is based in New York, but has manufacturing facilities in France – is developing what is called a product “allogenic” CAR-T. It is basically a universal line of T cells, at least in theory, could be deployed on anyone. The aim is to cut the extraction step patient’s own cells and reengineering them before putting them back into the body. If it works, it could save time and money.

“With allogeneic cell therapy, could have a manufacturing plant cells prepare ahead of time, so it can be used immediately for treatment,” said Julianne Smith, vice president of development CAR- T in Cellectis, who is working with Pfizer. “Certainly there is a great advantage here, because we could increase the accessibility.”

Cellectis allogenic products have been tested – successfully -. Two children with incurable leukemia otherwise, under a special provision of compassionate use

However, some experts doubt it will work on a larger scale. The construction of universal T cells that could work in any is, in a sense, as difficult as building a functional artificial kidney that can be implanted in any patient without fear of rejection. Our bodies may be too difficult to fool, Levine said.

“Certainly there is a fundamental reason for allogeneic therapies, but it is important to recognize that our immune system has evolved over several hundred million years to distinguish self from non-self,” Levine said.

“The idea that there will be this bank of cells, and that will be good for everyone as a permanent solution – which is far, if still possible.” Levine said

Breaking ground in factories

Other companies are moving in the more traditional model of customizing CAR-T. Juno Therapeutics, for example, opened a manufacturing site in Seattle who has the ability to serve the whole country, said Steve Harr, chief financial officer of juno. You could even provide CAR-T international therapies -. Provided Juno continues to focus on a relatively small niche of patients with blood cancers select

“We have invested heavily since a day, process development and manufacturing,” Harr said. “With our current processes and our current size, we can treat thousands of patients of this facility – but not tens of thousands.”

CAR-T Juno machines have a modular design that can be expanded as demand grows, he said. The vision of the company, however, is the construction of a single machine that can manufacture tailor therapies for patients with thousands of cells. Has a prototype in the works, but is not yet ready for prime time, Harr said.

Kite Pharma performed the groundbreaking for CAR-T factory near Los Angeles in June 2015, but has not yet made any large-scale manufacturing.

“We can manufacture cells? We’ve shown we can do it in an environment of clinical study,” said Dr. David Chang, medical director of the kite. “Can we climb and production of a large number of patients We have done as well as other [companies] -. And probably better, in terms of the preparations”

The company is now “move towards marketing and product launch, “Chang said.

Solid tumors are difficult


CAR-T depends in part on whether scientists can find a way to get it to work in solid tumors – as ovarian cancer and colon – which make up most of oncological diseases. This has proved extremely difficult.

“With CAR-T cells, we have a Ford Model T, but we need a Ferrari to get into solid tumors,” said Dr. Renier Brentjens, director of cell therapy at Memorial Sloan Kettering. He is working with Juno in your CAR-T treatment.

CAR-T works by designing T cells to go after a molecule that is found exclusively on the surface of a cancer cell -., But that can not be found on the surface of any cells healthy in the body

researchers have found that the key molecules, or antigens, for blood cancers like leukemia and lymphoma.

But when the National Cancer Institute attempted to treat a patient who had a specific mutation, known as HER2, linked to colorectal cancer, the patient died.

The problem, Goff explained was the HER2 protein was present not only in cancer cells but also in normal cells lining the heart. So when the CAR-T stuck to any cell containing the HER2 protein, which not only removed the cells of colon cancer, but also attack the tissues surrounding the patient’s heart.

“I think it’s precautionary, a case report,” Goff said.

Some of the specific antigens on the CAR-T therapy for blood cancers also appear in some healthy cells. But are usually the B cells, a component of the immune system – and humans can live without the B cells, if they have the right kind of support. After receiving the CAR-T therapy, patients receive injections of immunoglobulin, an antibody normally produced by B.


“Not that we found a magical way to treat leukemia and lymphoma,” said Goff. “It is only with solid tumors, the goals we have found – well, are also of the tissues that need They’re in the pancreas, in the structure of the heart or lungs -.. They are not tissues that can destroy without causing problems”

of course, it’s only the first day of the CAR-T therapy.

Another promising avenue, therapy T cell receptor or TCR, is also being developed by the kite, Cellectis, and many other players immunotherapy. They hope it could become more effective in the fight against cancers of solid tumors. TCR therapy works in theory, by penetration of a cancer cell. It allows the immune cells to attack scope to targets that are within a cancer cell cells.

However, cell therapies will both clinical success and commercialization to maintain momentum, Loncar said.

“What we have to consider: What Novartis and the kite and Juno trials have at this moment of truth is version 1.1 – and companies are learning every day from what they are seeing, “Loncar said. “Over time, new versions of this will come out. As a starting point, is extremely promising.”

Correction :. An earlier version of this story inaccuracy in which biotech firm Cellectis is based

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