Blocking TIGIT May Help With Dipping Remission Rates in NHL After CAR T-Cell Therapy

Investigators from the Mayo Clinic Cancer Center in Florida and at the Cleveland Medical Center confirmed that TIGIT drives chimeric antigen receptor (CAR) T-cell exhaustion and dysfunction, and it was further realized that blocking TIGIT with CAR-T cell therapy may improve treatment efficacy, according to a press release by Mayo Clinic.¹

The 2 organizations were researching possible causes for decreasing remission rates for patient with non-Hodgkin Lymphoma (NHL) who are treated with CAR T-cell therapy.

"CAR-T cell therapy is a promising treatment for non-Hodgkin lymphoma, especially for patients who have relapsed or those who have not responded to prior therapies," said Tae Hyun Hwang, PhD, a researcher at Mayo Clinic Cancer Center in Jacksonville, Florida.

Hwang continued with a cautionary note that after recent long-term follow-up data has seen potentially decreasing success rates of CAR-T cell therapy in patients with NHL. He said; "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."

"The overall goal of our research is to support precision oncology care. Novel therapeutic strategies will help us improve the efficacy of CAR-T cell therapy for patients with non-Hodgkin lymphoma," commented David Wald, MD, PhD, of Case Western, the co-author of the study, from the Cleveland Medical Center.

Hwang added, "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.

Investigators created single-cell RNA and protein sequencing data for CAR T cells before they were administered to patients and did throughout the study after being infused in patients. Hwang says this work generated more than 133,000 single-cell expression profiles, which researchers used to develop and apply computational approaches to further understand single-cell level RNA or protein expression patterns of CAR-T cells associated with treatment response.

Using these computational approaches, a gene and T cell called TIGIT was found that was highly expressed in post-infusion CAR-T cells from patients who did not respond to CAR-T cell therapy

"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 Hwang.

According to the study,CAR-T therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory NHL. Many patients receiving CD19 CAR-T cells, however, failed to respond for unknown reasons. Investigators initiated single cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and post-infusion into patients with NHL o reveal changes in 4-1BB-based CD19 CAR-T cells and identify biomarkers of response. Investigators observed the evolution of CAR-T cells toward a non-proliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. When utilizing in vitro and in vivo studies, TIGIT blockade alone improves the anti-tumor function of CAR-T cells. Investigators concluded that there is evidence of CAR-T cell dysfunction marked by TIGIT expression, driving a poor response in NHL patients.²

References:

_{1. Researchers seek to improve success of chimeric antigen receptor-T cell therapy in non-Hodgkin lymphoma. Press release. Mayo Clinic. May 12, 2022. Accessed May 17, 2022. https://mayocl.in/3MsTQVa}

_{2. 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. Published online May 12, 2022. Cancer Discov. 2022;candisc.1586.2021. doi:10.1158/2159-8290.CD-21-1586}