A Penn CAR-T patient later developed new cancer. Researchers are investigating.

The University of Pennsylvania detailed a case in which a blood cancer patient who was treated with a breakthrough gene therapy pioneered at Penn later developed another form of blood cancer in a journal study released on Wednesday.

The Food and Drug Administration is investigating at least 20 similar reports among patients treated with chimeric antigen receptor T cell, CAR-T, therapy. The makers of six commercial CAR-T therapies must include a boxed warning alerting patients of the risk, the FDA said Tuesday.

CAR-T therapy involves removing the body’s T cells — the white blood cells with a leading role in the body’s immune response — and genetically modifying them to target cancer cells. The approach has been hailed as a breakthrough treatment and possibly a cure for some types of blood cancer.

More than 34,000 patients worldwide have been treated with versions of the genetic engineering technique.

The emerging reports of secondary cancer in patients treated with CAR-T have researchers asking whether CAR-T treatment could be responsible, or whether the new cancers are unrelated.

CAR-T patients are inherently at greater risk for developing new cancers because they typically receive the treatment after trying chemotherapy, radiation, and other therapies that weaken the immune system.

But in the 20 cases flagged by the FDA, patients developed cancer in the type of white blood cells that were genetically modified as part of their treatment. The agency in November announced it was investigating whether the T cell cancers may have been caused by CAR-T therapy.

» READ MORE: FDA is investigating whether CAR-T, a cancer therapy pioneered at Penn, can cause lymphoma

In the Penn case, a 64-year-old man with non-Hodgkin B-cell lymphoma developed another form of the blood cancer in his T cells three months after receiving CAR-T therapy. Researchers who analyzed the case concluded that the new cancer was not caused by CAR-T.

Penn researchers studied an additional 449 CAR-T cases to better understand the risk of developing new cancers. An unedited version of their findings was published Wednesday in the journal Nature Medicine.

“While it’s an awful, devastating risk, it’s not at all clear it’s related to having gotten CAR-T cells,” said David Porter, the director of cell therapy and transplantation at Penn’s Abramson Cancer Center.

Penn cancer scientist Carl June was among the first researchers to discover a way to arm the body’s own immune system against cancer. His team treated its first adult leukemia patients with CAR-T in 2010. The first pediatric patient, Emily Whitehead, was cured of a deadly form of leukemia at the Children’s Hospital of Philadelphia and is now a freshman at the University of Pennsylvania.

» READ MORE: Emily Whitehead was the first child cured of cancer with therapy from Penn. She’s back as a freshman.

June and Michel Sadelain, who developed a similar approach at New York’s Memorial Sloan Kettering Cancer Center, were awarded a $3 million Breakthrough Prize for their discovery last year.

Penn treats patients with commercially available CAR-T therapies and also develops its own treatments in-house.

Pharmaceutical companies have used CAR-T technology to develop six drugs, all used to treat forms of blood cancer.

The new labeling requirement affects all six drugs:

The FDA has not yet published its findings about the 20 cases in which patients developed new blood cancers.

Prominent cell therapy experts, including Porter and his Penn colleagues, wrote in an opinion piece published by the journal Nature Medicine that they believe the risk is slight and far outweighed by the benefits of CAR-T therapy.

They also questioned whether CAR-T treatment caused the new cancer. People who receive CAR-T have highly compromised immune systems, which makes them more vulnerable to developing secondary cancers, they wrote.

Penn researchers analyzed 449 patients treated with CAR-T at the University of Pennsylvania to better understand the risk. Of those, 16 developed a new cancer within 26 months of treatment, almost all originating outside of the T cells.

Patients who were older than 65 years of age and had received at least three previous cancer treatments were more likely to develop secondary cancers, according to the study.

Researchers found only one case in which a patient developed cancer in T cells. They ruled out the possibility that it had been caused by CAR-T after removing the patient’s tumor and studying it. Researchers did not find any trace of genetically modified material in the tumor cells that could have come from the patient’s CAR-T therapy.

The patient ultimately died of an unrelated cancer.

Penn will be closely following the FDA’s investigation, Porter said. The hospital system already updated the consent forms that patients sign before treatment to make clear the risk of secondary cancer.

Porter does not think the new boxed warning will deter patients, but hopes it will lead to more cases being entered in the FDA Adverse Event Reporting System, a database that tracks medication safety.

The database helps the FDA identify potential safety problems with medications — such as the CAR-T patients who developed T cell cancers after treatment — but participation is voluntary.

Only 8,000 of the 34,000 people who have been treated with CAR-T are tracked in the database.