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.

Keywords: S100B; checkpoint inhibitor therapy; eosinophils; interleukin 6; irAE; macrophages; malignant melanoma; temporal correlation; tolerance breakage; treatment monitoring.

Figure 1

Analysis of temporal correlation of immune activation and release of biomolecules into the serum of cancer patients treated with checkpoint inhibition (CPI). t1: Start of CPI. CPIA: Administration of checkpoint inhibitors. C1: release of cancer-derived proteins or DNA in the absence of a response to CPI. C2: Release of cancer-derived proteins or DNA in response to CPI at time point t2. OTD1: Release of organ tissue derived biomolecules without immune mediated tissue damage. OTD2: Increase of organ tissue derived biomolecules due to treatment-induced and immune-mediated tissue damage at time point t3. I1: Continuous increase of immune activity under CPI. I2: Non-continuous phasic increase of immune activity under CPI.

Figure 2

Idealized model of cell cycle-dependent immune-mediated release of biomarkers during immunotherapy of cancer, adapted from [32].

Figure 3

Time course of immune markers c-reactive protein (CRP) and IL-6 and tumor markers S100B and lactate dehydrogenase (LDH) during checkpoint inhibitor treatment starting at day 0. Patient no. 1, four cycles of ipilimumab, delay in the administration of the fourth cycle was due to gastral bleeding.

Figure 4

Time course of immune, tumor and cell damage (creatine kinase (CK)) markers during checkpoint inhibitor treatment starting at day 0. Patient no. 5, 7 cycles of pembrolizumab.

Figure 5

Time course of immune and tumor markers during checkpoint inhibitor treatment starting at day 0. Patient no. 6, first four cycles of pembrolizumab.

Figure 6

Time course of immune, tumor and cell damage (ALT) markers during checkpoint inhibitor treatment. Patient no. 8, last two cycles of nivolumab; two cycles of nivolumab plus ipilimumab starting at day 0.

Figure 7

Time course of immune, tumor and cell damage (myoglobin (myog.)) markers during checkpoint inhibitor treatment starting at day 0. (A) Patient no. 15, fourth cycle of nivolumab; (B) Patient no. 16, first cycle of nivolumab plus ipilimumab combination treatment. MONO = monocytes.

Figure 8

Time course of immune and tumor cell damage markers during checkpoint inhibitor treatment starting at day 0 in patient no. 17 receiving four cycles of nivolumab plus ipilimumab combination treatment followed by nivolumab monotherapy. Interval between the first and second cycle was prolonged due to gastritis of unknown cause. For better visualization, S100B levels are plotted at ¼ of actual values. EOS = eosinophiles.