“Benchmark” research could help reduce complications of emerging immunotherapy.

In the first systematic study of its kind, researchers at Fred Hutchinson Cancer Research Center report comprehensive data on infectious complications of an emerging cancer immunotherapy strategy called CD19 CAR T-cell therapy.

Infections are a common, and often dangerous, side effect of many cancer therapies that can damage the immune system, including chemotherapy, bone marrow transplant and certain targeted drugs. Learning how to control these infections over the past decades has saved countless lives.

In CAR T-cell therapy, patients’ immune cells are genetically reprogrammed to kill their cancer cells. But aspects of the strategy, along with treatments patients may have received previously, can significantly impair the immune system, leaving patients vulnerable to infections.

“Understanding the impact of infectious complications of CD19 CAR T-cell immunotherapy is an important goal that will help us design safer ways to give CAR T cells in the future,” said Dr. Cameron Turtle, an immunotherapy researcher who is one of the study’s leaders. The new paper joins two others recently published by Turtle and his colleagues characterizing cytokine release syndrome and neurological side effects of CAR T-cell therapy.

The Fred Hutch–led team reported on three months of data from 133 adult patients with three different advanced, treatment-resistant blood cancers. The patients were enrolled in an ongoing trial of one CAR T-cell product conducted at the Fred Hutch/University of Washington Cancer Consortium.

The infection rate was highest in the first month after patients received their genetically engineered immune cells, with 43 infections in 30 patients. The incidence rate and types of infections they observed—which included bacterial, viral and fungal infections—were comparable to those seen in recent trials of other, non–T-cell treatments in similar cancer patients, the team reported. An infection caused or contributed to the deaths of two patients. Additional research will be required to better characterize the risks of late infections that occur longer after CD19 CAR T-cell therapy, the scientists said.

The researchers identified several independent risk factors for infection, including cancer type, number of prior treatments, CAR T-cell dose, and severity of cytokine release syndrome, or CRS—a CAR T-cell–related toxicity characterized by a spectrum of symptoms ranging from fever to life-threatening low blood pressure.

The rate of infections and their severity went down after the researchers optimized their dosing strategy to reduce the rates of CRS and related toxicity, they reported.

“Mitigating side effects of CAR T-cell therapy, such as CRS, and refining antimicrobial prophylactic approaches will likely reduce infectious complications,” said lead researcher Dr. Joshua Hill of Fred Hutch, who specializes in research to protect immune-compromised cancer patients from infection.

It’s unclear whether CRS is directly increasing risk for subsequent infections, he said, or whether other factors—such as hospitalization and supportive care measures required by patients with CRS—are contributing.

This new study sets a benchmark, Hill said, for the field to begin to make progress in understanding and reducing infectious complications of CAR T-cell therapies, just as cancer researchers have done before for other therapies.

“Some of the best advances we’ve made in long-term outcomes for cancer patients have been through tailored interventions to control infectious complications that would otherwise limit the use of lifesaving chemoimmunotherapies,” Hill said.

This study was published online in the journal Blood on October 16.