Correlative Monitoring of Immune Activation and Tissue Damage in Malignant Melanoma—An Algorithm for Identification of Tolerance Breakage During Immune Checkpoint Inhibitor Therapy of Cancer

Abstract

We describe an innovative approach for identification of tolerance breakage during immune checkpoint inhibitor therapy in malignant melanoma. Checkpoint inhibitor therapy enhances the immunologic clearance of cancer by suppressing pathways which induce immune suppression and tolerance. We posit that by analyzing temporal correlations of key markers of immune activation and tissue damage it would be possible to detect the onset of anticancer immune reaction as well as of immunologic adverse effects which might become crucial for optimization as well as safety of immune checkpoint inhibitor treatment. We analyzed time courses of routine laboratory values of serum tumor markers as well as of markers of immune activation in 17 patients with metastasized malignant melanoma receiving checkpoint inhibition and weekly laboratory controls. A parallel serum level increase of interleukin-6 and the tumor marker S100B could be identified in 13 patients, suggesting that the onset of tolerance breakage under checkpoint inhibition may be identified and measured. Immune-related adverse events in the patients were also accompanied by a peak of IL-6. In six patients, the onset of a putative anticancer immune reaction and the beginning of immunologic adverse events occurred in the same treatment cycle; in six patients the immunologic adverse reactions took place in separate cycles.

Risk Factors for Relapse after Intentional Discontinuation of Immune Checkpoint Inhibitors in Melanoma Patients

“…7 Although we cannot exclude that a larger cohort is required to detect a significant difference, our data are in line with the recent concept that response to ICI is an early event that can even occur after short-term treatment. 9 Furthermore, there is evidence that activation and clonal proliferation of T cells are early events during ICI treatment. 10 Taken together, these data suggest that treatment duration may not be relevant for the decision to stop ICI therapy.…”

Case Report: Lymphocytosis Associated With Fatal Hepatitis in a Thymoma Patient Treated With Anti-PD1: New Insight Into the Immune-Related Storm

“…We confirm the above-mentioned clinical behavior. It is therefore tempting to speculate about the role of laboratory evaluation with full blood cell count, liver function assessment, and a full endocrine panel in making repeated indirect snapshots in order to avert the dynamic immune-related toxicity onset ( 46 , 47 ). Thus, it is mandatory to better refine the druggable focuses, decreasing the incidence of undesired effects exerted by immune-system modulation and novel bullets striking the non-cancerous neighborhood.…”

Proteomics to study cancer immunity and improve treatment

“…Conversely, in the setting of ICIs, high CRP levels are generally linked to poor prognostic outcome and to immune-related toxicity [47,48]. Individual cytokines, most notably interleukin (IL)-6 and leukemia inhibitory factor (LIF), have been correlated to clinical outcomes of therapy but can be difficult to distinguish from immune-related toxicity [49][50][51][52][53]. The complexity is further increased by the fact that immunerelated toxicity and anti-tumor clinical efficacy are correlated outcomes [54].…”