A newly published study in Nature Medicine by researchers at the University of Pennsylvania has revealed a very rare but potentially troublesome side effect in CAR-T therapies. And according to experts, that could create challenges for the therapies’ manufacturers.
The study showed that a lentiviral vector that was supposed to bind to a young acute lymphoblastic leukemia patient’s T cells with a chimeric antigen receptor, or CAR, which enables them to target leukemia cells, instead bound to a single malignant B cell. That, in turn, may have given the cancerous CAR-expressing cell the ability to hide from the CAR-T cells by masking CD19, the antigen protein expressed by leukemia cells that the CAR-Ts target. Subsequently, the patient suffered a fatal relapsed, with all of the leukemic cells carrying the CAR.
The CAR-T, then in clinical development by the university, is currently marketed by Swiss drugmaker Novartis as Kymriah (tisagenlecleucel), having won Food and Drug Administration approval for pediatric ALL in August 2017 and for adult diffuse large B-cell lymphoma earlier this year. The patient, aged 20, was part of a university-sponsored clinical trial that completed in 2016.
While the risk of similar incidents happening today has decreased as Kymriah has transitioned from academia to industry, it could still be present, due to the risk of unwanted cells being present in the sample destined to become CAR-Ts.
“Since that patient’s product was made several years ago, and one can expect continuous process improvement, the probability of significant numbers of extraneous cells creeping through should reduce as these products mature,” said Anthony Davies, CEO and founder of Campbell, California-based Dark Horse Consulting, in a phone interview. “That said, one of the issues with this entire class of drugs is variability in the patient-specific starting material.”
Another CAR-T, Kite Pharma’s Yescarta (axicabtagene ciloleucel), was approved for DLBCL in October 2017, shortly before Kite’s $11.9 billion acquisition by Gilead Sciences.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
The issue, Davies said, is that different hospitals have different processes and favorite protocols for apheresis, meaning extraction of T cells. “So tightening up that funnel leading into the manufacturing process is something we feel is important for lowering levels of impurities and standardizing the product.”
Heidi Hagen, co-founder and chief strategy officer of San Francisco-based cell and gene therapy supply chain firm Vineti, said that while one can’t say such an incident won’t happen again, it is less likely now that the product is in industry hands, while even academic centers have become better at manufacturing. “Academic centers need more maturity in manufacturing, but industry will always be the most mature,” she said in a phone interview. In particular, that’s because it is under greater scrutiny from the FDA and has a lot of tough internal standards. “But I do think the academic centers are coming along – I don’t want to malign them,” she added.
In an emailed statement, Novartis said its manufacturing process is different from the one used at the University of Pennsylvania and is not aware of any similar cases happening among the more than 400 patients treated with Kymriah, which prior to approval was known as CTL019. The company said it has processes to remove B cells, including leukemic cells, from the apheresed product and steps to further limit B-cell presence, along with a registry for long-term monitoring and efforts to remove manufacturing variability.
At the same time, Davies said that while the apparently low frequency of such incidents may not be a problem for patients who have exhausted other therapy options, it could become an issue should the CAR-Ts win approval for earlier lines of therapy. Currently, Kymriah and Yescarta are approved for patients who have failed or relapsed after multiple lines of treatment, but the natural history for most drugs is to win FDA approval for their use in less heavily pretreated patients. “That is a bigger ask,” he said. “It’s one thing to have a small chance of something going wrong in a patient with a few months to live, but that’s another thing to say to a patient who’s just embarking on therapy.”
Hagen also said it will raise the stakes. “When you start talking about frontline therapies and going into very large solid tumor indications, there’s going to be a much larger bar,” she said.
Photo: nopparit, Getty Images
