Dive Brief:

The inadvertent genetic engineering of a single leukemic cell during clinical manufacturing of a CAR-T cancer therapy led to fatal treatment resistance in one patient, researchers at the University of Pennsylvania reported Monday, highlighting the thin margin for error in producing the cutting-edge medicines.

The patient, who was enrolled in a Phase 1 study of what would become Novartis' CAR-T therapy Kymriah, initially responded to treatment, but relapsed nine months later and eventually died. Researchers traced the relapse to the unintentional introduction of a leukemic B cell during production of personalized cell therapy.

While a single report, the findings demonstrate the critical importance of manufacturing to CAR-T and suggest a possible mechanism of resistance to cell therapy. In a statement, Novartis emphasized the methods it uses for commercial production of Kymriah differ from those used by Penn in clinical testing.

Dive Insight:

Produced using a patient's own immune cells, CAR-T therapy is critically dependent on how it's manufactured. The process is complex, involving the genetic engineering and expansion of patient T cells ex vivo before infusion back into the body.

In the case reported by Penn, however, a single cell compromised the entire process. Researchers involved in the Phase 1 study of Kymriah (tisagenlecleucel) linked the fatal relapse of a 20-year-old man with acute lymphoblastic leukemia to the inadvertent inclusion of a leukemic cell in the engineering of that patient's T cells.

For Kymriah, T cells are genetically altered to seek out and attack leukemia cells that express a surface protein known as CD19. Unintentionally modifying that single cancer cell to express an anti-CD19 receptor as well enabled the cell to escape detection and multiply, researchers concluded.

Nine months after treatment and a complete response, the patient relapsed due to the growth of leukemia cells resistant to CAR-T.

Researchers ruled out other possible causes of resistance, such as mutations or alternative splicing in CD19, and judged the relapse to stem from a single blast clone transduced with CAR19 vector during manufacturing.

"These findings illustrate the need for improved manufacturing technologies that can purge residual contaminating tumor cells from engineered T cells," the researchers wrote.

The manufacturing error appears to be rare, however. Only the one patient out of 369 treated patients reported at time of publication experienced such a case of treatment resistance.

Novartis also emphasized that it's improved its manufacturing process to avoid exactly this type of misstep.

"The Novartis manufacturing process is different from the academic manufacturing process used at Penn," wrote the Swiss pharma in an emailed statement. "We have processes in place to eliminate B-cells, including leukemic cells, from the apheresed product and have steps throughout the manufacturing process to further limit the risk of B-cell presence."

The pharma said it wasn't aware of any cases of this happening in the more than 400 patients treated with Kymriah using Novartis' manufacturing process.

Still, the case report underscores how the science behind CAR-T is still emerging.

"It's another demonstration of the unique (and often unforeseen) challenges of cell therapies, especially autologous therapies derived from cancer patients," said Michael Gladstone, a principal at Atlas Venture who has experience with immuno-oncology, in emailed comments to BioPharma Dive.

"However, it sounds like this has already been addressed by Novartis's manufacturing improvements. This reflects the rapid pace of engineering progress in this arena," he added.

Novartis has, however, reported other unrelated manufacturing issues tied to meeting product specifications laid out by the Food and Drug Administration for commercial use of Kymriah in diffuse large B-cell lymphoma.