When oncologist Dr. Carl June heard the Food and Drug Administration’s decision to bring the first gene therapy to market in the US, he pinched himself, hard.

“It was so improbable that this would ever be a commercially approved therapy,” he said, voice breaking with emotion.

June was referring to a revolutionary cancer therapy that he helped bring from lab bench to market. Co-developed with the drug giant Novartis, the therapy, CAR-T, genetically alters a patient’s own immune cells to target and destroy cancer cells.

Recently, in a historic decision, the FDA threw their support behind Kymriah (tisagenlecleucel), a “living drug” that is designed to treat blood and bone marrow cancer in children that, even with aggressive chemotherapy, is often lethal.

An entire process rather than a packaged pill, the therapy harvests a patient’s own immune cells—T cells that patrol and destroy abnormal cells—retrains them with extra bits of genetic code, and turns them into torpedoes aimed at cancerous cells once reintroduced into patients’ bodies.

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Dr. Scott Gottlieb in a statement, adding that the therapy is “the first gene therapy available in the United States.”

But the story isn’t all rosy.

Several deaths in early trials have tainted CAR-T’s wonder drug status, and Kymriah poses serious risks. Because the treatment has to be made individually for each patient, researchers worry that production may not be able to keep up. What’s more, the $475,000 one-time treatment price tag (somewhat more affordable than the two approved gene therapies in Europe) is still far too “excessive” for the average consumer.

Nevertheless, the FDA’s announcement was met with much fanfare. To Dr. Bruce Roth at the Washington University School of Medicine, who served as an advisor to the FDA’s panel on CAR-T, the benefits far outweigh the risks.

“Although I have some concerns about late toxicity, you have to be a long-term survivor to be concerned about late toxicity,” he says. “And I think that’s what this drug gets us.”

Souped-up Killers

In a nutshell, CAR-T gives each patient an individualized immune system that works “better than nature made it,” says June.

The therapy extracts T cells, soldiers of the immune system, from a patient’s blood. While T cells normally hunt down cancerous rogues within the body, they’re not all that smart: cancers often “learn” to disguise themselves and evade the attack.

Back in the 1980s, Dr. Zelig Eshhar at the Weizmann Institute of Science first tried his hand at genetically doctoring T-cells to give them a boost. Using viruses, he infected the cells with genetic code that allowed them to pump out special proteins to their surfaces that researchers call “chimeric antigen receptors,” or CARs.

These insertions do two things: they zap the T-cells into action and allow them to more effectively hunt down and destroy tumors by grabbing onto their surface markers.

That’s how you turn normal T-cells into “serial killers,” where a single one can destroy up to 100,000 cancer cells, says June.

Novartis’s Kymriah is tailored to a specific type of blood cancer: B-cell acute lymphoblastic leukemia. B-cells are the workhorses behind antibodies—proteins that seek out and neutralize infections. But when these good guys go rogue, the result is a highly aggressive type of tumor that strikes about 600 children and young adults in the US a year.

B-cells, whether healthy or cancerous, have a protein called CD19. Almost a decade ago, June and his team pieced together genetic code to produce a complex protein—a chimera—made from different parts of the immune system that acts like a claw to grab onto CD19.

“I call it a Frankenstein-like molecule,” says Dr. Renier Brentjens at Memorial Sloan Kettering Cancer Center.

To get the monster into cells, June took a daring approach: he turned to HIV.

Using the AIDS virus for this kind of treatment is natural because it evolved to invade T-cells, says June. The crux was to gut it of its viral powers, so that it transforms into a tool that infects immune cells but doesn’t reproduce itself. The resulting carrier (dubbed a “vector”) is a true “Rube Goldberg-like solution,” made up of different bits of DNA from humans, mice, and cows that together turn the sinister HIV virus benign.

In a process that takes about 22 days, T-cells extracted from patients are exposed to the vector, which genetically transforms them. They’re then expanded and frozen for shipment back to the patient. Meanwhile, the patients receive chemotherapy to wipe out their remaining T cells, as the native population may interfere with the expansion of their super-counterparts.


“The patient becomes a bioreactor,” says June, explaining that as the engineered T-cells proliferate, they release a storm of immune molecules called cytokines that help destroy B-cells and cause flu-like symptoms.

The T-cells stick around after their work is done, homing to the bone marrow where they retain their memory of the attack for at least six months: if cancerous B-cells come back, they’re ready for another go.

Clinical Success

Eager to push his therapy to market, June collaborated with Novartis in a series of clinical trials. An earlier trial in 2011 sparked hope as two of three patients with chronic lymphocytic leukemia went into complete remission.

“We had to order another biopsy to be sure; we couldn’t believe it,” recalls June.

Then, in an unpublished trial in 2015, 52 out of 63 participants—a hefty 82.5 percent—went into overall remission following treatment with Kymriah within three months. By six months, almost 90 percent of the treated patients were still alive, and at one year, 79 percent survived.

The trial ran without a control group, meaning that the investigators could not accurately say how effective the treatment is. Nevertheless, the results were promising enough to sway a panel of expert advisors, who unanimously recommended the FDA to approve Kymriah on July 12, 2017.

“This is a major advance, and is ushering in a new era,” said panel member Malcolm Smith, a pediatric oncologist at the National Institutes of Health at the time.

Others worry that the community may once again be misled by the glimmering hope of gene therapy.

A worrying 47 percent of participants in the 2015 trial experienced a life-threatening inflammatory reaction known as cytokine storm, which causes symptoms such as high fever and organ failure in extreme cases.

In trials with therapies similar to Kymriah, these side effects have resulted in brain swelling and deaths, casting a shadow over the field. Seizures and hallucinations were also relatively common, though temporary, and Novartis reports that the side effects can be successfully managed with a drug called Actemra.

CAR-T also poses the thorny challenge of drug quality control: how to  standardize the potency and purity of living cells extracted from each patient?

Because of these risks, the FDA is requiring hospitals and personnel dispensing the therapy to be certified. Within a month, Kymriah will be available at 20 US hospitals, and that number is expected to increase to 32 total sites by the end of the year. Novartis is also required to conduct a post-marketing observational study in patients treated with Kymriah to further evaluate long-term safety.

So far, the therapy is only available for patients 25 years or younger who don’t respond to conventional therapies or relapsed while on those therapies.

The individualized nature and relatively small patient population both drive up the cost of Kymriah, says science journalist John Horgan. The high price tag is illustrative for gene therapies as a whole: because different diseases have different genetic mechanisms, each presents a new problem to be tackled from scratch—Kymriah, for example, may not work on T-cell leukemia.

Although scientists are working towards “off-the-shelf” cell therapies, in which killer cells can be engineered from donors rather than individually made, their efforts are stymied by a series of tragic deaths prompting regulatory agencies to shut down the trials.

Unless scientists devise a way to scale these individualized therapies, patients will inevitably be burdened with startling drug costs.

Without doubt, Kymriah comes with a high price tag and even higher risks. But it may extend the lives of young patients who have few other alternatives.

“This is a big paradigm shift, using this living drug,” says Dr. Kevin Curran, a pediatric oncologist at Memorial Sloan Kettering Cancer Center that will soon be offering the treatment. “It will provide a lot of hope. This is the beginning.”

Stock Media provided by sergunt / Pond5

Shelly Xuelai Fan is a neuroscientist at the University of California, San Francisco, where she studies ways to make old brains young again. In addition to research, she's also an avid science writer with an insatiable obsession with biotech, AI and all things neuro. She spends her spare time kayaking, bike camping and getting lost in the woods.

Follow Shelly: