By the time Cameron Lahti sat down to receive CAR T-cell therapy, he’d been through six-and-a-half years of chemotherapy. “For him, it was an average day,” says his mother, Debbie Dean-Lahti. “He played video games or watched a movie. It wasn’t intrusive at all.” Cameron already had a Hickman line—a central venous catheter often used to administer chemotherapy—so there wasn’t even a needle involved. Instead, a syringe was attached to the line and in went the T-cells. “It was just a simple push,” says Debbie.
But that day was far from average for Cameron. Because that was the first day of his longest chemo-free remission to date: two-and-a-half years and counting. After being diagnosed with B-cell acute lymphoblastic leukemia in 2010 at age three, Cameron spent three-and-a-half years in chemotherapy. He relapsed six months after completing treatment, and started a second round of chemotherapy in 2014. Two years later, he relapsed again, while still in chemotherapy. Typically the next line of treatment would be a bone marrow transplant, but the family had another option, a new genetic treatment called CAR T-cell therapy. With support from the Hospital for Sick Children, they travelled to Philadelphia where Cameron took part in a clinical trial, the only way to receive CAR T-cells at the time.
It looks like that’s about to change. In September, Health Canada authorized the commercial use of a CAR T product called tisagenlecleucel (trade name Kymriah) for adults with relapsed or refractory diffuse large B-cell lymphoma and for children and young adults (ages three to 25) with relapsed or refractory ALL. On Tuesday, the Canadian Agency for Drugs and Technology in Health, which conducted a health technology assessment of tisagenlecleucel, recommended that it be funded for Canadian patients so long as the price is lowered and certain conditions around implementation are met—as groundbreaking as CAR T-cell therapy is, it’s also incredibly complex and expensive to deliver. And in many ways, it has yet to be proven.
What is CAR T-cell therapy?
CAR T-cell therapy is a “precision medicine” treatment, meaning treatment that is tailored to individual patients. It also belongs to a new group of cancer treatments known as immunotherapy. In CAR T, a person’s T-cells—which are among the body’s most important immune cells—are taken from their blood, and then infused into the person’s bloodstream. CAR stands for “chimeric antigen receptor,” which is the extra genetic matter added to the T-cells. CARs allow T-cells to detect and kill cancer-carrying cells, which can otherwise be difficult to identify. Once in the bloodstream, CAR T-cells continue to multiply, and this is why the treatment is sometimes referred to as a “living drug.”
Why is there so much excitement about it?
CAR T-cell therapy has shown some very promising results in the treatment of blood cancers. In one tisagenlecleucel trial, 82 percent of the 79 children with ALL who received the treatment were in remission three months after the infusion; at 18 months, the overall survival rate was 70 percent. In another, 40 percent of 93 adults with diffuse, large B-cell lymphoma showed a “complete response” a year after the treatment. Both trials were single-arm and both were supported by Novartis, the Swiss-based pharmaceutical company that manufactures and has the patent for Kymriah.
But what is most exciting about these results is that the patients who participated in these studies were unresponsive to or had relapsed multiple times after receiving chemotherapy and/or bone marrow transplant. “CAR Ts have opened up a new treatment option for us for kids who are otherwise untreatable,” says Donna Wall, pediatric hematologist and section head of the bone and marrow transplant program at Sick Kids Hospital. “We’re definitely seeing kids—and we always hesitate using the cure word—who we had absolutely no other options for.”
As promising as CAR T-cell therapy is, it comes with many complications. The wait time between extraction and infusion can be two to four months, or even longer, says Wall. During that time, a patient’s treatment goes into what she calls a “holding pattern.” They need to be given “just enough and not too much” chemotherapy. “For me, [this] is one of the harder parts of treatment,” says Wall. “If you think of it, these kids all have really bad leukemia. And they’ve already failed many lines of treatment. It’s often very hard to keep them in some level of disease control.”
There can also be difficulties with manufacturing. “About 20 percent of the kids who we start to try to make CAR Ts for, we’re not able,” says Wall. “The number of T-cells that a patient has in their circulation that we can collect, and the use and the function of those cells, is something that we can’t control,” she explains.
And then there are the side effects. Almost a third of the patients Wall sees will have a very serious complication called cytokine release syndrome, in which what is sometimes called a “storm” of cytokine proteins flood into the bloodstream as a result of T-cells at work. “Basically the T-cells are doing too good a job,” says Wall. While CRS can be a sign that the CAR therapy is working, it can lead to severe problems with blood pressure, fever, organ function, and possible brain inflammation. It is usually treatable and typically short-lived, but requires immediate attention. Patients must be closely monitored for at least a month after infusion, and many are admitted to hospital for this monitoring period.
CAR T-cell therapy is known as a “one-time treatment”—once the cells are in your body, they’re there to stay. But some patients receive a second infusion, as Cameron Lahti did, when it was discovered, six months after the first infusion, that he had some “baby B-cells” in his system. People who receive CAR T have their B-cells checked regularly and can expect to receive a weekly or monthly infusion of immune globulin for the rest of their lives. “As long as the CAR Ts are working, the [patient] will not make IG, and so we have to give that replacement,” says Wall.
In addition to these treatment complexities, there are a number of logistical challenges that come with administering tisagenlecleucel. For example, cost. Tisagenlecleucel is priced at $475,000 in the U.S., and £282,000 in the U.K. The price submitted to CADTH for Canada by Novartis is confidential. But as Harindra Wijeysundera, vice-president of medical devices and clinical interventions at CADTH, told the Globe and Mail in December, the drug’s price is only part of the cost of delivering the treatment. Other expenses include pre- and post-infusion monitoring—which to date have typically been inpatient—and also transportation and accommodation for patients to the centres authorized by Novartis to provide the treatment. Currently only five provinces in Canada have such facilities.
How can the system accommodate such a complex and expensive treatment?
Whatever price Novartis submitted to CADTH for consideration, CADTH thinks it’s too high. The report released on Tuesday recommends a 10 percent decrease in the price of the product for its application in ALL, and a 45–65 percent decrease for its application in diffuse large B-cell lymphomas. Following the release of the report, a representative from Novartis responded to Healthy Debate’s query about the Canadian price of tisagenlecleucel by email: “The list price for Kymriah is not yet final. Novartis is working collaboratively with Canadian authorities to set the final prices for Kymriah in Canada. Novartis is committed to ensuring the timely and responsible adoption of Kymriah in the Canadian healthcare system and to bringing Kymriah to patients in Canada in a sustainable manner.” Cancer Care Ontario is currently negotiating the final price or prices to be paid in Canada with Novartis on behalf of all the provinces, and CADTH’s recommendations will help inform these negotiations.
Part of the reason for the recommended price decreases is the relative newness and scarcity of evidence behind tisagenlecleucel. For both applications, CADTH makes the point that, “Given the lack of long-term follow-up data, the single-arm study design of the pivotal trial, and the limited number of patients in the studies, there is uncertainty in the clinical and economic evidence.” CADTH has also recommended that tisagenlecleucel be reassessed for both indications, with standardized outcomes being collected in a pan-Canadian registry which “uses a defined set of outcomes and definitions to generate real-world evidence” so as to better understand “longer-term effectiveness, safety, and cost-effectiveness.” The nature of this reassessment—who pays for it, who owns the data—will be discussed by provincial and territorial representatives with Novartis, Wijeysundera explained on Tuesday. These representatives are part of an ad-hoc committee appointed by the deputy ministers of health to decide whether and how to operationalize the introduction of tisagenlecleucel in Canada, a process that will be informed both by CCO’s negotiations with Novartis and by CADTH’s recommendations.
Could CAR T-cell therapy replace chemotherapy as the standard of cancer care?
After receiving CAR T-cell therapy, Cameron Lahti asked his parents why he didn’t receive it in the first place. “It’s easier than chemotherapy,” he told the Newmarket Era this past September.
Cameron responded very well to CAR T, but some kids are too sick—their T-cells too compromised—to benefit from it, after months or years of having the disease and of being treated with chemotherapy. “Will it work better if we treat earlier in the course of kids’ leukemia?” says Donna Wall. “Nobody knows. Will we be able to replace bone marrow transplants? Will we be able to replace the three years of chemotherapy?”
Nobody knows—yet. What is clear, though, is that after decades of development, CAR T-cell therapies are about to start sprouting up like daffodils in the spring. Health Canada is already looking at a second one called axicabtagene ciloleucel (trade name Yescarta), which has been recommended for commercial use by the FDA in the U.S., and which has applications for non-Hodgkin’s lymphoma. And it’s been reported that there are at least 20 CAR T-cell therapies currently “moving through clinical trials toward FDA review.”
“There’s potential in the future for these [therapies] to be effective not just against leukemia and lymphoma, but also against many other much more common types of cancer, the so-called solid tumours—lung, breast, colon, brain,” says Rob Holt, professor of medical genetics at UBC and Simon Fraser University. “They haven’t yet been developed to the state where they work well in all cancers, but those barriers are going to fall. And the question becomes, in Canada in particular, if we have a universal health care system, how could these therapies become universally available?”
Holt is the project lead in health care implementation research currently being funded by the non-profit BioCanRx that is exploring whether it’s possible to design, manufacture and deliver CAR T-cell therapies within a public health care system. His team recently submitted a proposal to test what is essentially the equivalent of a generic CAR T-cell therapy in a clinical trial. “More and more people are seeing that this just isn’t going to fly in the universal health care systems,” says Holt. “So, some patients, those in greatest need, will be able to get the therapy and it will be reimbursed, but then what happens 10 years or 20 years down the road when now all cancer needs to be treated this way? It has the potential to be front-line therapy, basically replace conventional chemotherapy, at least for some, maybe most, patients.”
If that holds true, imagine the difference that might make in the future for a patient like Cameron Lahti, who for the past two-and-a-half years has been healthy—playing video games at home after school rather than in hospital while receiving chemotherapy. “For the first time, in a very long time, we are able to look forward,” says his mother, Debbie.