TIGIT Blocking Could Improve CAR T-Cell Response in NHL

Researchers have demonstrated that chimeric antigen receptor (CAR) T-cell dysfunction marked by TIGIT (T cell immunoreceptor with Ig and ITIM domains) expression may be driving poor response to the therapy in patients with non-Hodgkin lymphoma (NHL).

Despite the promise of CAR T-cell therapy for patients with NHL, long-term follow-up data suggest that the success rate for patients with NHL 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 Tae Hyun Hwang, PhD, a researcher at Mayo Clinic Cancer Center in Jacksonville, Florida.

To explore mechanisms of poor response, the researchers conducted single-cell RNA sequencing and protein surface marker profiling of patient CAR T-cells both pre- and post-infusion. They generated more than 133,000 single-cell expression profiles that the researchers then used to develop and apply computational approaches to dissect single-cell RNA or protein expression patterns of CAR T-cells associated with treatment response.

Using these computational approaches, the team found that a gene called TIGIT was highly expressed in post-infusion 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 NHL and may also improve patient survival,” Dr. Hwang said.

Sources: Mayo Clinic Press Release, May 2022

Jackson Z, Hong C, Schauner R, et al. Sequential single cell transcriptional and protein marker profiling reveals TIGIT as a marker of CD19 CAR-T cell dysfunction in patients with non-Hodgkin’s lymphoma. Cancer Discov. 2022. doi:10.1158/2159-8290.CD-21-1586