Expression of T-Cell Exhaustion Molecules and Human Endogenous Retroviruses as Predictive Biomarkers for Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma.

Abstract

PURPOSE:

We sought to validate levels of CD8+ tumor-infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (IF biomarker; Pignon and colleagues, 2019) and to investigate human endogenous retroviruses (hERV) as predictors of response to anti-PD-1 in a randomized trial of nivolumab (nivo) versus everolimus (evero) in patients with metastatic clear cell renal cell carcinoma (mccRCC; CheckMate-025).

EXPERIMENTAL DESIGN:

Tumor tissues (nivo: n = 116, evero: n = 107) were analyzed by multiparametric immunofluorescence (IF) and qRT-PCR. Genomic/transcriptomic analyses were performed in a subset of samples. Clinical endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and durable response rate (DRR, defined as complete response or partial response with a PFS ≥ 12 months).

RESULTS:

In the nivo (but not evero) arm, patients with high-IF biomarker density (24/116, 20.7%) had higher ORR (45.8% vs. 19.6%, P = 0.01) and DRR (33.3% vs. 14.1%, P = 0.03) and longer median PFS (9.6 vs. 3.7 months, P = 0.03) than patients with low-IF biomarker. By RNA sequencing, several inflammatory pathways (q < 0.1) and immune-related gene signature scores (q < 0.05) were enriched in the high-IF biomarker group. When combined with the IF biomarker, tumor cell (TC) PD-L1 expression (≥1%) further separated clinical outcomes in the nivo arm. ERVE-4 expression was associated with increased DRR and longer PFS in nivo-treated patients.

CONCLUSIONS:

High levels of CD8+ TIC expressing PD-1 but not TIM-3 and LAG-3 and ERVE-4 expression predicted response to nivo (but not to evero) in patients with mccRCC. Combination of the IF biomarker with TC PD-L1 improved its predictive value, confirming our previous findings.

• Authors: Miriam Ficial, Opeyemi A Jegede, Miriam Sant'Angelo, Yue Hou, Abdallah Flaifel, Jean-Christophe Pignon, David A Braun, Megan Wind-Rotolo, Maura A Sticco-Ivins, Paul J Catalano, Gordon J Freeman, Arlene H Sharpe, F Stephen Hodi, Robert J Motzer, Catherine J Wu, Michael B Atkins, David F McDermott, Sachet A Shukla, Toni K Choueiri, Sabina Signoretti
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 5 Pg. 1371-1380 (03 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33219016 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Viral Envelope Proteins
• Nivolumab
• Everolimus

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (metabolism)
• Carcinoma, Renal Cell (drug therapy, immunology, metabolism, secondary)
• Endogenous Retroviruses (metabolism)
• Everolimus (administration & dosage)
• Female
• Follow-Up Studies
• Humans
• Kidney Neoplasms (drug therapy, immunology, metabolism, pathology)
• Lymphocytes, Tumor-Infiltrating
• Male
• Nivolumab (administration & dosage)
• Prognosis
• Retrospective Studies
• Survival Rate
• T-Lymphocytes (immunology)
• Transcriptome
• Viral Envelope Proteins (metabolism)