A study published by Jackson et al in Cancer Discovery investigated the reasons for decreased remission rates for patients with non-Hodgkin lymphoma treated with chimeric antigen receptor (CAR) T-cell therapy.
"CAR T-cell therapy is a promising treatment for non-Hodgkin lymphoma, especially for patients who have relapsed or for those who have not responded to prior therapies," said study coauthor Tae Hyun Hwang, PhD, a researcher at Mayo Clinic Cancer Center in Jacksonville, Florida. However, Dr. Hwang explained that recent long-term follow-up data suggest that the success rate of CAR T-cell therapy for patients with non-Hodgkin lymphoma may be decreasing.
"Lasting remission in this setting ranges from 30% to 40%, so it is critical to identify a predictive biomarker to measure CAR T-cell resistance, so we can better match patients with effective therapy," said Dr. Hwang.
Dr. Hwang continued, “Our team hypothesized there would be distinct molecular patterns in CAR T cells between patients who responded to treatment and patients who did not respond.” He said the team used innovative computational and experimental approaches to identify these patterns.
Researchers generated single-cell RNA and protein sequencing data for CAR T cells before they were administered to patients and again at multiple points after being infused in patients. Dr. Hwang said this work generated more than 133,000 single-cell expression profiles that researchers used to develop and apply computational approaches to dissect single-cell level RNA or protein expression patterns of CAR T cells associated with treatment response.
Role of TIGIT
Using these computational approaches, the team found that a gene called TIGIT—a T cell—was highly expressed in postinfusion CAR T cells from patients who did not respond to CAR T-cell therapy. The team also validated that TIGIT drives CAR T cell exhaustion and dysfunction, and they discovered that blocking TIGIT with CAR T-cell therapy could improve treatment efficacy in an in vivo study.
"If our findings can be validated in prospective clinical trials, our TIGIT-blocking strategy with CAR T-cell therapy may improve current CAR T-cell therapy responses in patients with non-Hodgkin lymphoma and may also improve patient survival," concluded Dr. Hwang.
Disclosure: For full disclosures of the study authors, visit aacrjournals.org/cancerdiscovery.
