T Helper 17 (TH17) cells have emerged as a potential biomarker for predicting the risk of immune-related adverse events (irAEs) in patients with metastatic melanoma receiving combination therapy with nivolumab (Opdivo), ipilimumab (Yervoy), and tocilizumab (Actemra). The findings, presented at the 2024 American Society of Clinical Oncology Breakthrough meeting, also suggest that regulatory T (Treg) cells, GP130, IL-6, and osteopontin could serve as markers to monitor treatment response and efficacy.
IL-6 Blockade and Improved Outcomes
Teruyuki Mizutani, MD, PhD, of New York University Langone Medical Center, explained the rationale behind the study: "High levels of IL-6 are found in the serum of patients with metastatic melanoma and other cancers. Circulating IL-6 levels are associated with poor outcome in immune checkpoint inhibitors. Our aim was to investigate the effect of tocilizumab, an IL-6 receptor antagonist, on immune checkpoint inhibitors."
The phase 2 S19-00008 trial (NCT03999749) involved 70 patients with metastatic melanoma. Results indicated that IL-6 receptor blockade with tocilizumab preserved progression-free survival (PFS) and overall survival while reducing irAEs when combined with ipilimumab and nivolumab. The estimated 2-year survival rate was 75%, and the best overall response rate, as determined by RECIST v1.1, was 57% with a median follow-up of 23 months. The median PFS was 9.1 months, and the duration of response had not yet been reached.
Biomarker Analysis
In the open-label study, peripheral blood mononuclear cell (PBMC) samples were collected at baseline, week 7, and week 37 and categorized by irAE severity and clinical response (severe irAEs [grades 3-5], the absence of toxicity or lower-grade irAEs [grades 1-2], clinical benefit, and nonclinical benefit). According to Mizutani, the study aimed "to identify biomarkers that can predict response and grade 3 to 4 irAEs and to find the mechanism of irAEs."
Investigators observed that patients with high levels of IL-6 and osteopontin in their classical monocytes at baseline tended to have shorter overall survival. Furthermore, the quantity of TH17 cells was significantly higher in patients who experienced severe irAEs at baseline and in those who experienced no or lesser-grade toxicity. Treg cells significantly increased after immunotherapy. The researchers highlighted blocking IL-6 as a method to enhance the effectiveness of immune checkpoint inhibitors (such as nivolumab and ipilimumab) against the tumor, potentially reducing the toxicity associated with these treatments.
The immune monitoring protocol utilized enzyme-linked immunosorbent assay to measure IL-6, GP130, IL-23, osteopontin, and the Luminex oncological panel (LXSAHM-22). Multiparametric flow cytometry was used to analyze myeloid cells, cytotoxic T cells, and checkpoint protein expression on immune cells. Data acquisition was performed using Sony’s ID7000 cytometer, followed by quality control, normalization, and clustering using FlowJo software.
Treatment Regimen and irAE Incidence
Patients received tocilizumab (4 mg/kg) every 6 weeks throughout the trial, intravenous (IV) ipilimumab (1 mg/kg) every 3 weeks, followed by IV nivolumab (3 mg/kg) every 3 weeks for the induction phase. The maintenance phase included 240 mg of nivolumab every 2 weeks for 12 to 24 weeks, then 480 mg of nivolumab every 4 weeks for up to 2 years.
"Unexpectedly, grade 3 to 4 severe irAEs, which led to treatment discontinuation, occurred in 22% [of patients] in our study, and in the CheckMate 067 [NCT01844505] and CheckMate 511 [NCT02714218] trials, it was between 33% and 59%," Mizutani noted. The reported grade 3 and 4 irAEs by week 24 included lipase/amylase elevation (n = 2), aspartate aminotransferase/alanine aminotransferase elevation (n = 4), pneumonitis (n = 1), colitis (n = 2), diarrhea (n = 4), adrenal insufficiency (n = 1), skin/rash (n = 1), and alkaline phosphatase elevation (n = 1).
Future Directions
"Tocilizumab may reduce the onset of threatening irAEs such as colitis, myocarditis, or type 1 diabetes," Mizutani stated. "The success of [the] S19-00008 [trial] has led to study S22-00325 [NCT05428007], which includes the luxury antibody with a phase 2 lead-in of 33 patients followed by a 1:1 [randomization] of immuno-oncology triplet drugs with or without IL-6 receptor blockade with sarilumab (Kevzara)."
