CAR T-Cell Therapy May Be Less Successful in Patients With Immune Dysregulation

February 23, 2021

Resistance to chimeric antigen receptor (CAR) T-cell therapy in patients with diffuse large B-cell lymphoma (DLBCL) may be associated with tumor and systemic immune dysregulation, according to investigators from Moffitt Cancer Center in Tampa, Fla. 

Clinical studies of CAR T-cell therapy have shown overall response rates of more than 80% in patients, and an ongoing response of nearly 40% two years after therapy. In this observational study, investigators sought to determine why some patients have a better CAR T response than others and what can be done to improve the treatment’s effectiveness. They published their findings this month in Blood.

Investigators collected and analyzed blood and tumor samples from 105 patients treated with axicabtagene ciloleucel (Yescarta, Kite Pharma), the first CAR T-cell therapy approved to treat DLBCL. They categorized patients into two groups: durable responders who remained in remission at a minimum follow-up of six months after infusion, and nondurable responders who experienced relapsed lymphoma.

Findings suggested that large tumors led to immune dysregulation in these patients due to chronic interferon signaling within the tumor and high cytokine levels in the patient. They also determined that CAR T-cell therapy was less likely to be successful overall in patients with immune dysregulation. They attributed this to impaired growth of CAR T cells in these patients and the tumor’s resistance to CAR T-cell therapy due to the expression of multiple immune checkpoints.

“These findings could help improve the way we administer CAR T therapy on two fronts. We can use interventions to help improve the quality of patients’ immune cells prior to apheresis, resulting in a better CAR T product,” said Michael Jain, MD, PhD, assistant member of the Blood and Marrow Transplant and Cellular Immunotherapy Department at Moffitt. “We can also help better prepare patients’ immune systems to receive the CAR T cells to increase response following infusion.”

According to the researchers, more study is needed to determine what those interventions would be, but they hope that these findings can help modify therapy to reduce patient relapse after CAR T-cell administration.