Low Peripheral TCR Clonality Linked to Improved Survival With Atezolizumab

CHICAGO — In patients with metastatic urothelial carcinoma treated with atezolizumab, low peripheral T-cell receptor (TCR) clonality was associated with survival, while high T-cell infiltration and clonality in the tumor plus peripheral expansion of dominant tumor-resident TCR clones correlated with response, according to data presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

“Programmed death-1 (PD-1) pathway blockade has robust activity in patients with pretreated, metastatic urothelial carcinoma,” said lead investigator Samuel Funt, MD, medical oncologist at Memorial Sloan Kettering Cancer Center in New York, NY. “PD-L1 expression correlates with response rate but lacks sufficient sensitivity and specificity, thus requiring improved predictive biomarkers.”

Therefore, investigators sought to determine if the T-cell repertoire in tumors and blood correlates with clinical outcomes. To do so, they analyzed specimens from 29 patients with metastatic urothelial carcinoma who received atezolizumab 1200 mg IV every 3 weeks as part of the IMvigor 210 study. Specifically, researchers performed high-throughput DNA sequencing of the CDR3 region of the TCR beta chain in baseline tumors using ImmunoSEQ assay, and assessed clonal dominance, clonal expansion, and T-cell fraction for an association with benefit.

Results showed that the median number of T cells and unique TCRs sequenced in tumors was 1402 and 1085, respectively. The median number of T cells and unique TCRs sequenced in plasma bone marrow cells was 147,493 and 81,705, respectively.

Researchers found that a combination of high T-cell infiltration and clonality in tumors was associated with complete or partial response compared with progressive disease (OR, 11.5; P=.02232). 

The study also demonstrated that patients with lower baseline peripheral TCR clonality had improved progression-free survival (P=.0514) and overall survival (P=.0116). Further, the number of T-cell clones in the tumor that expanded in the blood 3 weeks after atezolizumab therapy was greater among patients who achieved a complete or partial response than in those with stable disease or those with progressive disease.

“In the pretreatment blood, low T-cell receptor clonality is associated with improved survival, and in the pretreatment tumor, high T-cell infiltration and clonality are associated with response,” Dr Funt explained. “In the blood during treatment, expansion of tumor-infiltrating lymphocyte clones is rapid and more robust in responding patients.”

Dr Funt concluded that these findings ultimately highlight the complexity of the antitumor immune response and warrant further study.

Reference

1. Funt S, Charen AS, Yusko E, et al. Correlation of peripheral and intratumoral T-cell receptor (TCR) clonality with clinical outcomes in patients with metastatic urothelial cancer (mUC) treated with atezolizumab. J Clin Oncol. 2016; 34 (suppl; abstr 3005).