TH17 Cells May Serve as Biomarker in Metastatic Melanoma

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T Helper 17 (T_H 17) cells may be a potential biomarker to predict the risk of immune-related adverse events (irAEs) in patients with metastatic melanoma receiving the combination therapy of nivolumab (Opdivo), ipilimumab (Yervoy), and tocilizumab (Actemra). Regulatory T (Treg) cells, GP130, IL-6, and osteopontin may also serve as markers to monitor treatment response and efficacy, according to data from the phase 2 S19-00008 study (NCT03999749). Data were presented by Teruyuki Mizutani, MD, PhD, at the 2024 American Society of Clinical Oncology Breakthrough meeting held from August 8 to 10, 2024, in Yokohama, Japan.¹

“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,” Mizutani, of New York University Langone Medical Center in New York, said during the presentation of the data.

The trial involved 70 patients with metastatic melanoma, and trial results found that IL-6 receptor blockade with tocilizumab preserved progression-free survival (PFS) and overall survival and reduced 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.

In the open-label study, investigators collected peripheral blood mononuclear cell (PBMC) samples at baseline, week 7, and week 37 and categorized them by irAE severity and clinical response. The categorization consisted of severe irAEs (grades 3-5), the absence of toxicity or lower-grade irAEs (grades 1-2), clinical benefit, and nonclinical benefit. “We aimed to identify biomarkers that can predict response and grade 3 to 4 irAEs and to find the mechanism of irAEs,” Mizutani said, outlining the study’s goals.

Patients who had high levels of IL-6 and osteopontin in their classical monocytes at the start of the study tended to have shorter overall survival, according to investigators. This was observed through the clustering of myeloid cells. Investigators also observed that the amount of T_H 17 cells are significantly higher in the patients who experienced severe irAEs at baseline and in patients who experienced no toxicity or lesser-grade toxicity. Treg cells significantly increase after immunotherapy. Investigators highlighted blocking IL-6 as a method to enhance the effectiveness of the immune checkpoint inhibitors (such as nivolumab and ipilimumab) against the tumor, potentially reducing or separating the toxicity commonly associated with these types of treatments.

The immune monitoring protocol used enzyme-linked immunosorbent assay to measure IL-6, GP130, IL-23, osteopontin, and the Luminex oncological panel (LXSAHM-22). Investigators used a multiparametric flow cytometry to analyze myeloid cells, cytotoxic T cells, and checkpoint protein expression on immune cells. Approximately 1 million PBMCs per sample were processed with different antibodies, and data acquisition was carried out with Sony’s ID7000 cytometer. The data then underwent quality control, normalization for PBMCs per patient, concatenation, dimensionality reduction, and clustering using FlowJo software.

Patients in the trial received tocilizumab (4 mg/kg) every 6 weeks through the full course of the trial, then intravenous (IV) ipilimumab (1 mg/kg) every 3 weeks followed by IV nivolumab (3 mg/kg) every 3 weeks for the induction phase of the trial. The maintenance phase included 240 mg of nivolumab every 2 weeks for a duration of 12 to 24 weeks and 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 said.^2,3 The reported grade 3 and 4 irAEs by week 24 were 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).¹

“Tocilizumab may reduce the onset of threatening irAEs such as colitis, myocarditis, or type 1 diabetes,” Mizutani said. “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).”

REFERENCES:

1. Mizutani T, Muramatsu T, Handzlik J, et al. Predictive and pharmacodynamic biomarkers for combination therapy in stage IIIIV melanoma: a Simon phase II trial (NCT03999749). American Society of Clinical Oncology Breakthrough; August 8-10, 2024; Yokohama, Japan.

2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546. doi:10.1056/nejmoa1910836

3. Lebbé C, Meyer N, Mortier L, et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: results from the phase IIIb/IV CheckMate 511 trial. J Clin Oncol. 2019;37(11):867-875. doi:10.1200/jco.18.01998