Thursday, June 16, 2022

University Hospitals Seidman Cancer Center researchers part of team finding blocking a single receptor may combat T-cell dysfunction associated with poor response to therapy
 

Improvement in chimeric antigen receptor (CAR) T-cell efficacy in patients with non-Hodgkin lymphoma may be achieved through inhibition of a single receptor, TIGIT, linked to T cell exhaustion, according to a new study from investigators at UH Seidman Cancer Center. Published in Cancer Discovery, the study further reports that TIGIT is highly expressed in CAR-T cells isolated from patients with a poor response to therapy, suggesting its expression may serve as a biomarker of patient outcome.
 
“These findings represent a novel strategy to overcome CAR-T cell resistance and may help more patients with non-Hodgkin lymphoma benefit from this life-saving immunotherapy,” said David Wald, MD, PhD, Associate Director for Basic Research at the Wesley Center for Immunotherapy at University Hospitals Seidman Cancer Center, and an Associate Professor of Pathology and a member of the Immune Oncology Program at Case Comprehensive Cancer Center. Wald is also an associate professor of pathology at the Case Western Reserve University School of Medicine.
 
CAR-T cell therapy can offer durable remission for patients with non-Hodgkin lymphoma who relapse or fail to respond to chemotherapy or other prior treatment. Yet long-term follow-up data suggests the success rate of CAR-T cell therapy for patients with non-Hodgkin lymphoma may be decreasing, said Tae Hyun Hwang, PhD, a researcher at Mayo Clinic Cancer Center and a co-author on the study.

“Lasting remission in this setting ranges from 30 to 40 percent, so it is critical to identify a predictive biomarker to measure CAR T-cell resistance so we can better match patients with effective therapy,” Dr. Hwang said.

In the new study, the research team used single-cell RNA sequencing and protein surface marker profiling to assess how changes in CAR-T cells pre- and post-infusion correlate with response to treatment. All samples were collected from patients with non-Hodgkin lymphoma receiving treatment at University Hospitals Seidman Cancer Center and done at the Cellular Therapy Lab jointly operated by the Wesley Center for Immunotherapy at UH Seidman Cancer Center and the National Center for Regenerative Medicine at Case Western Reserve. This state-of-the-art cell manufacturing facility is capable of generating CAR T-cells in an expedited fashion and at reduced cost.

Compared to patients with a favorable response to therapy, CAR-T cells from patients with progressive or stable disease displayed signs of T cell dysfunction after infusion.
 
“Of the extensive panel of exhaustion markers tested, TIGIT was the most differentially expressed between favorable and poor responders,” said Dr. Wald. “We also noticed an overexpression of the inhibitory receptor PD1 and several transcription factors associated with T cell exhaustion, including TOX, NR4A2, EOMES, and PRDM1.”
 
The study is the first to demonstrate improvement in CAR-T cell efficacy in mouse models with TIGIT inhibition alone and with a therapeutic monoclonal TIGIT blocking antibody. An additional strength of the study is the evaluation of TIGIT expression from CAR T-cells derived from the blood rather than tumor tissue, making it a potentially minimally invasive biomarker.
 
“We’re now looking to clinical trials to validate our strategy for improving CAR T-cell efficacy with TIGIT blockage, not only for non-Hodgkin lymphoma but other malignancies as well,” said Dr. Wald.