Xconomy National

The first ever approval of a new kind of cancer immunotherapy called CAR-T is one step closer. A 10-member panel of doctors and researchers who advise the Food and Drug Administration recommended with a rare unanimous vote that the agency approve a treatment for kids and young adults with a severe form of leukemia who have run out of other options.

The therapy would involve genetically modifying a patients T cells to kill cancer and then infusing them back into the body. The dramatic effect of the treatment, known for years as CTL-019, was never questioned at the meeting. Of 68 young people receiving it, 52 of them had an excellent response almost immediately, with their cancer disappearing within the first three months. Three-quarters of those patients remained cancer-free six months after treatment.

Explaining their vote, many advisors were effusive. Its the most exciting thing Ive seen in my lifetime, said Timothy Cripe, a blood cancer and bone marrow transplant specialist at Nationwide Childrens Hospital in Columbus, OH.

Others had high praise for the drugs marketer, Novartis (NYSE: NVS), and its plans to keep a close eye on the potentially severe side effects of CAR-T if it becomes a commercial product. Those so-called risk mitigation plans were one of the main concerns that the FDA, in documents released Monday, asked its advisors to consider.

The main side effect of CTL-019 is cytokine release syndrome, a blistering immune reaction to the drug and the detritus of dying cancer cells. It can be deadly, with spiking fevers and other symptoms, if medical staff arent properly trained for it. Novartis said it would train staffers at 30 to 35 medical centers and take other measures, as well.

At the FDAs behest, the advisory panel spent much of the day discussing long-term side effects, toothe possibility that the T cell modification could go awry, and years down the road cause secondary cancers. Its a concern that stems from the early days of gene therapy, when the genetic tweaking of patients cells with a modified virus turned on cancer-causing genes.

Novartis officials said they would follow patients for at least 15 years and investigate any cases of secondary cancers. Committee member Catherine Bollard, who runs an immunotherapy center at the Childrens Research Institute in Washington, DC, said she would like Novartis also to investigate when patients relapse with altered forms of leukemia.

The committee members said it was hard to assess the long-term risk, but in patients with no other treatment options, the near-term benefits of CAR-T therapy more than tipped the scales. You have to be a long-term survivor to experience [long-term] toxicity, said Bruce Roth of the Washington University School of Medicine in St. Louis, MO. CTL-019 should give kids with ALL a chance for long-term survival, he said.

In a field that has plenty of pressing questions about severe, even deadly short-term side effects including brain swelling that was seen in trials of CAR-T therapies run by competing companies many observers were left wondering why the FDA highlighted the long-term risks of the CAR-T causing another cancer, perhaps years into the future. One possibility is that the agency is anticipating that CAR-T products will be developed for patients who arent at the end of the line. For example, the engineered T cells could be used as an adjuvant or additional therapy after a previous treatment has wiped out all but the last traces of cancer, said Richard Maziarz, a blood cancer specialist at Oregon Health and Science University in Portland.

In those settings, the downstream effect [of triggering a secondary cancer] is conceivable, said Maziarz. (Maziarz was not part of todays advisory committee. He has treated adult patients with CTL-019 as part of a different Novartis study.)

The news today buoyed Novartis stock, which was up $1.22, or nearly 1.5 percent. Based in Switzerland, but with much of its R&D in the U.S., Novartis was the first biopharma group to dive into the CAR-T field in a big way when in 2012 it launched a collaboration with the University of Pennsylvania. Much of the early work on CTL-019, now renamed tisagenlecleucel, took place in the universitys labs and clinics.

Novartis disbanded its cell and gene therapy group last year but vowed to press on with CTL-019. Approval in pediatric ALL now seems all but assured; the FDA rarely bucks the advice of its advisory committees. Novartis is also vying to have CTL-019 approved to treat adults with the most common forms of non-Hodgkin lymphoma. Beyond that, the companys plans with CAR-T are unclear. Penn has a next-generation CAR-T under development, dubbed CTL-119, which is not licensed to Novartis.

Novartis also convinced the advisory committee that its complicated manufacturing process could be fast and consistent. There are many links in the production chain, which requires extracting T cells from a patient, shipping them to a lab for genetic modification, making viral vectors that insert new DNA into the T cells, then shipping the cells back to be dripped through an IV back into the patient.

Such a complex system for making personalized treatments is likely to drive up their cost, and the next big hurdle (assuming an FDA approval this fall) is to win over insurers. The complexity can also introduce other kinds of risk, such as failure of the cells to repopulate the patients immune system. I think it will be important in the commercial phase to assess both failure rates and turnaround times for CAR-T production, said Krishna Komanduri, director of the Sylvester Comprehensive Cancer Center Adult Stem Cell Transplant Program at the University of Miami, who has treated patients with other experimental CAR-Ts, but not the one from Novartis. Either delays or failure of production will have clinical consequences for the highest risk patients.

Photo by Guido Van Nispen via Creative Commons 2.0 license.

Alex Lash is Xconomy's National Biotech Editor. He is based in San Francisco.

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Unanimous Advice To FDA: Approve Landmark CAR-T Cancer Therapy - Xconomy