CAR-T Clinical Trial Results Indicate 60% of Patients Suffered Adverse Effects, Including One Patient Death

A patient participating in a clinical trial involving an experimental CAR-T therapy drug has died of respiratory failure, but researchers are not certain if the death was directly tied to the use of the drug.

Chimeric antigen receptor (CAR) T cell therapy is a type of immunotherapy treatment that uses genetically modified immune cells, known as T-cells, to locate and destroy cancer cells. The altered gene therapy is approved for use in patients with advanced, difficult-to-treat, or reoccurring lymphoma, leukemia, and multiple myeloma blood cancers.

There are currently six FDA-approved treatments among the drug class, which include Abecma (idecabtagene vicleucel), Breyanzi (lisocabtagene maraleucel), Carvykti (ciltacabtagene autoleucel), Kymriah (tisagenlecleucel), Tecartus (brexucabtagene autoleucel), and Yescarta (axicabtagene ciloleucel). These treatments were approved under the requirement that the FDA conduct a 15-year observational study to assess the potential for long-term adverse health outcomes and secondary malignancies that could occur after treatment.

However, in January, the U.S. Food and Drug Administration (FDA) ordered several manufacturers to add black box warnings to all CAR-T drugs, indicating that the side effects may increase the risk of T-cell malignancies, which can result in hospitalization and death. The decision came after the agency’s researchers found 22 cases of secondary cancer linked to CAR-T side effects.

Despite the concerns, a panel of FDA scientific advisors recently determined that the benefits of CAR-T therapy outweigh the potential cancer risks.

Lyell Immunopharma is currently in phase 1 clinical trials for an investigational CAR-T therapy drug known only as LYL797. It announced the initial phase 1 trial data in a press release late last month, revealing that, despite promising results otherwise, one patient has died after developing grade 5 respiratory failure.

The patient was one of 20 participating in the clinical trial, 16 of whom had previously been diagnosed with triple-negative breast cancer, while four others had non-small cell lung cancer. All of the patients selected for the clinical trial had undergone six previous types of therapy and had relapsed or developed refractory metastatic disease.

In addition to the death, which researchers are unsure was linked to the investigational CAR-T medication, researchers reported a high number of adverse events among participants.

Adverse events led to more than 60% of patients developing cytokine release syndrome (CRS), with most cases being of mild severity, the researchers noted.

The researchers also determined that pneumonitis was the second most common adverse event, affecting about 22% of participants, and was the most frequently documented toxicity grade 3 or higher severity side effect. However, this was only detected in patients with triple-negative breast cancer who also had lung metastases.

Despite the concerns, the manufacturer still holds out promise for the new drug, indicating that there were no “dose-limiting toxicities” in patients who did not have lung problems.

The researchers noted that throughout all doses, the investigational drug had a clinical benefit ratio (CBR) of 38%.

CAR-T Therapy Drug Problems

The data comes after the FDA began an investigation into CAR-T cancer risks in November 2023, due to concerns over secondary cancer rates.

By December 31, the agency had found 22 cases of T-cell cancers linked to treatment with CAR-T products, including T-cell lymphoma, T-call large granular lymphocytosis, peripheral T-cell lymphoma and cutaneous T-cell lymphoma. All of the cases examined in detail to date appear to have manifested within two years of treatment.

Some of the cases are still under investigation, but cancer incidents have been reportedly linked to five of the six CAR-T cell drugs on the market, including Abecma, Breyanzi, Carvykti, Kymriah and Yescarta. The sixth drug, Tecarus, had no cases of cancer linked to it, but the FDA required it to also carry a black box warning anyway.

The agency warns that the cases are still under investigation, and raised concerns that postmarketing reports may underestimate the number of cancer cases caused by the drugs.

As a result of the risks associated with side effects of Carvykti and other CAR-T treatments, the FDA currently recommends that patients or clinical trial participants receiving these treatments be monitored for the rest of their life by a health care professional for new cancers that may develop.