Rare manufacturing glitch raises concern over CAR-T therapies: study

By Julie Steenhuysen

CHICAGO (Reuters) - A single leukemia cell inadvertently got mixed in with a batch of a patient's immune cells that were being manufactured into a CAR-T cell therapy and it acquired resistance to the treatment with deadly results, University of Pennsylvania researchers reported on Monday.

The mishap occurred in a 20-year-old leukemia patient treated with cells manufactured at the university, eventually causing a fatal relapse of the blood cancer, researchers reported in the journal Nature Medicine.

The patient was entered in an early-stage trial of CTL019, a treatment eventually licensed to Novartis and sold under the brand name Kymriah, which became the first such gene therapy to win U.S. approval in 2017.

Dr. Marco Ruella of the Center for Cellular Immunotherapies at the University of Pennsylvania, who led the study, said the case was "exceptionally rare," noting that it is the only one out of hundreds of patients treated at Penn.

He said the findings were disclosed to the U.S. Food and Drug Administration and discussed in detail prior to the treatment's approval.

CAR-T therapies, shorthand for chimeric antigen receptor T-cell, are part of a hot new approach to fighting cancer in which doctors remove infection-fighting immune cells known as T-cells, genetically engineer them to recognize and attack cancer, and infuse them back into the patient.

The personalized one-time treatment is complex and expensive, but offers hope for people with certain blood cancers who have exhausted all other treatment options.

Kymriah is approved in Europe and the United States to treat gravely ill children with acute lymphoblastic leukemia (ALL), as well as adults with diffuse large B-cell lymphoma (DLBCL).

Gilead Sciences' CAR-T therapy Yescarta also won U.S. and European approvals last year to treat DLBCL. Many more CAR-Ts are in clinical trials, including a multiple myeloma treatment being developed by Bluebird Bio along with Celgene Corp .

In the Penn study, researchers found that a single leukemia cell got processed along with the immune cells and infused back into the patient. In that process, the leukemia cell acquired the ability to hide from disease fighting CAR-T cells.

The patient was in his third relapse after earlier receiving chemotherapy and a cord blood transplant. Initially, he responded to the CAR-T treatment, but the altered leukemia cell grew unchecked, eventually causing the patient to relapse again.

The authors said the study illustrates the need for better manufacturing technologies "that can purge residual contaminating tumor cells from engineered T cells."

Novartis stressed that the company has a different manufacturing process than that used by Penn, and that its process includes steps to eliminate leukemic cells from the product.

"We are not aware of any cases of this happening in the more than 400 patients treated with CTL019/Kymriah manufactured by Novartis for clinical trials or the commercial setting," the Swiss drugmaker said in a statement.

(Reporting by Julie Steenhuysen; additional reporting by John Miller in Zurich; Editing by Bill Berkrot)