IL-6 and C-reactive protein as potential biomarkers for checkpoint inhibition

Medical writer: Muriel Cunningham

Elevations of C-reactive protein (CRP) and interleukin-6 (IL-6) are associated with poor outcomes in cancers such as melanoma, lung, colorectal, and breast. CRP is synthesized in the liver in response to different stimuli, including IL-6. To further explore the associations between IL-6, CRP, and patient outcomes, an investigation was conducted using samples from patients with melanoma enrolled in three studies of checkpoint inhibitors. Jeffrey S. Weber, MD, PhD, of the Laura and Isaac Perlmutter Cancer Centre, NYU Langone Medical Centre, presented the results of this study (Abstract 100).

Pretreatment and on-treatment serum samples from patients with melanoma enrolled in the following three studies were analysed: CheckMate-064 (140 patients; NCT01783938), CheckMate-066 (418 patients; NCT01721772), and CheckMate-067 (945 patients; NCT01844505). Levels of CRP and IL-6 were measured using Luminex multiplex panels. Analyses of the associations between CRP and IL-6 levels and patient response or survival were determined using Kaplan-Meier analysis.

In the initial analyses of CheckMate-064, modest associations between IL-6 and best overall response (BOR) were seen at baseline and on treatment. Higher baseline levels of IL-6 were seen in patients with a BOR of stable disease/progressive disease/not evaluable compared with patients who had a BOR of complete response or partial response in both cohorts at week 13, when the planned switch occurred. Additional analyses of the associations of IL-6 with survival in CheckMate-064 were subsequently performed, which found that high baseline or on-treatment levels of IL-6 were associated with poor survival. Similar results were seen when samples from the two larger trials were tested. “This is not a predictive marker; this is a baseline prognostic marker,” Dr. Weber said. Associations were also seen with CRP in all three studies, with high CRP levels leading to shorter overall survival. The results presented for both biomarkers are summarized in the Table.

In vitro experiments were conducted to determine why CRP might be associated with poor survival. Treating cells isolated from patients with melanoma with CRP indicated that CRP suppressed T-cell and dendritic cell function, decreased the generation of antigen-specific T cells, and inhibited calcium influx in T cells. “If you treat the dendritic cells, [CRP] suppresses antigen presentation. Treat the T cells, it suppresses T-cell aggregation. Treat both and combine them in an ex vivo assay, [and] you basically abrogate completely the ability to generate T-cell reactivity,” Dr. Weber said. A prospective clinical study to follow up on the IL-6 and CRP findings is planned.

Discussant Charles G. Drake, MD, PhD, of Herbert Irving Comprehensive Cancer Centre, agreed that the data indicate that IL-6 and CRP are prognostic biomarkers in melanoma and may be able to aid in patient selection. He noted that a key development advantage is that CRP is already a widely available, validated test approved by the U.S. Food and Drug Administration. Using the medians as cut points is appropriate for the early stages of biomarker development, but these parameters should be further refined. “There could be additional work to look at cut points and power calculations including positive and negative predictive value,” Dr. Drake said.



Posted on 15 July 201927 March 2024