A recent study identified TIGIT as a marker of chimeric antigen receptor (CAR) T-cell exhaustion and found it to improve CAR T-cell therapy efficacy in preclinical models.
While chimeric antigen receptor (CAR) T-cell therapy elicits significant responses and produces durable remissions in a significant subset of leukemia, lymphoma, and myeloma patients, the mechanisms behind instances of early disease relapse are still unclear. A recent study published in Cancer Discovery assessed the potential mechanisms of decreased remission rates after CAR T-cell therapy in non-Hodgkin’s lymphoma (NHL).
CAR T-cell therapy significantly changed the treatment landscape for certain cancer types, including leukemia and lymphoma. Currently, 6 CAR T-cell therapies are FDA approved for certain relapsed or refractory hematological malignancies, including NHL.
“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,” Tae Hyun Hwang, PhD, study author and researcher at Mayo Clinic Cancer Center in Jacksonville, Florida, said in a statement.
Patients who undergo CD19-targeted CAR T-cell therapy are approximately 30-40% likely to have a durable remission — and recent long-term follow-up data suggest the success rate may be decreasing. Thus, identifying predictive biomarkers to measure CAR T-cell resistance and inform treatment strategies is crucial, Hwang noted.
The study analyzed pre- and post-infusion CAR T-cell samples from patients with both positive and poor outcomes to assess single-cell transcriptomics and cell surface protein expression. Detailed analysis of single cells sets this study apart from others that have evaluated infusion products rather than transcriptional profiles and phenotypes of single CAR T cells. “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,” Hwang said.
The CAR T cells were analyzed with single-cell RNA and protein sequencing before and at multiple time points after infusion. Based on previous studies, days 14 and 30 were chosen due to their association with peak CAR T-cell expansion and peak contraction, respectively. The study samples included 13 patients with positive responses and 4 patients with poor responses to treatment.
Researchers found that the CAR T cells showed transcriptional heterogeneity and underwent notable changes after infusion. A main finding was that CAR T cells from patients who had poor responses to therapy showed an exhaustion profile differing from cells in patients who responded well to therapy. T cell immunoreceptor with immunoglobulin and ITIM domain
(TIGIT) was the most significant marker for the exhaustion profile. Upon further analysis, CAR T cells with high TIGIT expression had higher dysfunctional scores than CAR T cells with lower TIGIT expression, suggesting TIGIT blockade as a potential strategy to improve CAR T-cell effectiveness.
An in vitro chronic stimulation model and an in vivo mouse model of human NHL were used to test TIGIT inhibition’s effect on CAR T-cell exhaustion. TIGIT inhibition improved CAR T-cell anti-tumor function, further suggesting TIGIT expression could be a marker of T-cell dysfunction and poor response in patients with NHL.
The study was limited by a small number of poor responders but suggests TIGIT could be a potential target to boost CAR T-cell therapy efficacy. More research is still necessary to assess CAR T-cell efficacy and exhaustion over time across response groups, as well as the clinical potential of the TIGIT inhibition approach 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,” Hwang said.
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. Published online May 12, 2022. doi:10.1158/2159-8290.CD-21-1586