Background/Purpose:

The clinical use of immune checkpoint inhibitors (ICI) has led to outstanding clinical outcomes in previously refractory cancers, but ICI have also been associated with off-target side effects collectively known as immune related adverse events (irAE). Any organ system can be affected by these events during or after cessation of these therapies. Although management of these adverse events with immunosuppression is usually successful, our understanding of the underlying pathophysiology is incomplete. Furthermore, our ability to predict which patients will develop irAE is limited. The purpose of this study was to identify predictive biomarkers of irAE in cancer patients initiating ICI.

Methods:

Patients with advanced cancer scheduled to begin treatment with ICI were recruited from a tertiary care oncology centre. A detailed review of their electronic medical record was performed to record demographics, disease details, and treatment history (including drug names, start and stop dates, last dose, disease response). Serum was collected prior to initiating ICI therapy. Anti-nuclear antibodies (ANA) were detected using a common platform in the Mitogen Diagnostics Lab (Calgary, AB) and cytokines/chemokines were measured using a Human Cytokine/Chemokine 65-Plex panel (Eve Technologies, Calgary, Alberta). Subjects were followed prospectively and any irAE, defined by Common Terminology Criteria for Adverse Events (CTCAE), were recorded. Associations between clinical and serological biomarkers, and irAE were analyzed using t tests and ANOVA.

Results:

A total of 26 patients with advanced cancer were enrolled in this study. The mean age was 60 years old and 9/26 (35%) were female. Cancer types included melanoma (n = 13), renal carcinoma (n = 7), non-small cell carcinoma (n = 2), ovarian cancer (n = 2), Merkel cell carcinoma (n = 1), anal carcinoma (n = 1). All patients received therapeutic blockade of either PD-1 (n = 22) or PD-L1 (n = 4). irAEs occurred in 15/26 (58%) of the patients as follows: dermatitis (n = 1), colitis (n = 3), hepatitis (n = 2), hypothyroidism (n = 6), pneumonitis (n = 2), and type 1 diabetes mellitus (n = 1). The distribution of irAE grades were as follows (CTCAE grade 1 irAEs were excluded): CTCAE grade 2 (n = 9) and CTCAE grade ≥ 3 (n = 6). While males developed more grade 2 irAEs (n = 8), females developed more severe grade 3 irAEs (n = 4). Tumor type and the presence of ANA were not found to predict the development of irAE. On the other hand, sCD40L (p = 0.0413), PDGF-A (p = 0.0215) and PDGF-B (p = 0.007) were significantly higher prior to initiating ICI in patients who developed irAE compared to those who did not.

Conclusion:

These findings identify sCD40L, PDGF-A and PDGF-B as potential predictive biomarkers for the development of irAE in patients receiving ICI treatment for advanced cancer. Interestingly, although it has been shown that sCD40L is elevated in advanced cancers such as non-small cell lung cancer and also in various autoimmune disease, these data are the first to implicate it as a predictive biomarker for irAE development. The mechanisms by which these biomarkers participate in the onset of irAE needs to be explored.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elevated-scd40l-as-a-predictive-biomarker-of-immune-related-adverse-events-in-patients-receiving-immune-checkpoint-inhibitors/