Last week, Novartis’ CAR-T immunotherapy, Kymriah (tisagenlecleucel), was approved for children and young adults with relapsed B-cell acute lymphoblastic leukemia (ALL). The excitement was palpable as this first gene therapy and next generation immunotherapy got the FDA nod.

But this week, the FDA held up two Cellectis phase 1, CAR-T trials for UCART123 after one patient died from adverse effects associated with the treatment and another had a severe reaction.

These contrasts highlight the bumpy ride CAR-T therapies may face on their way to approval. UCART123 is by no means dead – the trial protocols can be redesigned to ease side effects. But CAR-T represents a high-risk/high-reward strategy to take on cancer.


“These are very potent drugs, good and bad,” said Sandip Patel, medical oncologist and assistant professor of medicine at the UC San Diego Moores Cancer Center, in a phone interview. “Good in terms of their effects on the cancer but bad if the side effects get out of control. Unfortunately, people can die from these side effects.”

Kymriah made it through trials with no such complications and benefits from being a late-stage treatment aimed mostly at children. Though the $475,000 price tag has raised some eyebrows, it is not inconsistent with what bone marrow transplants cost.

“It’s actually lower than some of us anticipated, given the earlier estimates,” said Madelyn Hanson, manager, Oncology Consulting Services, Clinical and Scientific Assessment at Kantar Health, in a phone interview. “It’s not out of line compared to what a stem cell transplant would be, and that’s something that commonly happens with relapsed/refractory ALL patients.”

Novartis gains the advantage of being first to market, but the Swiss company also has the added pressure of figuring out how this new class of therapy fits into the medical oncology toolkit. For example, they are working on a system in which payers would only reimburse them if patients respond.

“I haven’t seen the official policy, but if it doesn’t work, they actually won’t charge the insurer, which has never happened in cancer before,” Patel said. “It’s kind of the ‘Novartis money-back guarantee.’”

In fact, the news release announcing the drug’s approval approached the value/pricing issue head-on.

“Novartis is collaborating with CMS to make an outcomes-based approach available to allow for payment only when pediatric and young adult ALL patients respond to Kymriah by the end of the first month,” the press release noted.

“They’ll be the ones to pave the way and, I’m sure, figure out the logistics around it,” Hanson said of this payment model. “A lot of companies are watching very closely.”

The company may also benefit from the small ALL population, giving them the opportunity to walk before they run.

“There are about 2,500 cases of ALL in pediatrics and young adults a year,” Patel said. “The standard therapies work for around 2,000 of them, so we’re really only talking about 500 to 600 patients who would be getting CAR-T therapy, at least in this specific population.”

In the Cellectis trials, the patient who died was being treated for blastic plasmacytoid dendritic cell neoplasm (BPDCN), which has no specific treatments. The 78-year-old man experienced a number of adverse reactions, including cytokine release syndrome (CRS) and capillary leak syndrome, which are known CAR-T side effects. Last year, Juno Therapeutics faced similar problems with their ALL CAR-T therapy, JCAR015, which caused fatal cerebral edemas in three patients.

These reactions may underscore the need to more aggressively prescribe drugs like Roche’s Actemra (tocilizumab), which has been approved to treat CRS. Others have suggested embedding mechanisms that could deactivate these therapies.

“With the Cellectis and Juno products, they couldn’t turn those cells off once they started misbehaving,” Patel declared. “Do they need to have a suicide switch? It’s a question we must ask ourselves as we look to versions 2.0, 3.0 of these products.”

Despite CAR-T’s growing pains, it offers tremendous potential to help patients with few options.

“This is a game-changing therapy,” said Patel. “This technology is going to cure a lot of people with advanced disease that even bone marrow transplants couldn’t help.”