Investigational Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Event Prediction and Diagnosis

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of multiple cancers. However, these promising therapies may also cause immune-related adverse events (irAEs) in a substantial proportion of patients. These autoimmune phenomena may affect almost any organ system and may occur at almost any point in therapy. In some instances, these toxicities are life-threatening and potentially permanent. Diverse clinical presentation and unpredictable timing further complicate their anticipation and diagnosis.

Content: To improve patient safety and selection for ICI use, biomarkers for irAE diagnosis and prediction are under development. Clinicians may use traditional laboratory markers such as routine chemistries, creatinine clearance, thyroid function tests, and serum cortisol/adrenocorticotrophic hormone to monitor for specific irAEs, but noted aberrations may not necessarily represent an immune-mediated etiology. Novel biomarkers have the potential to be more specific to assist in the diagnosis of irAEs. The prediction of irAEs is more challenging. Apart from a history of autoimmune disease, no other clinical parameters are routinely used to project risk. Biomarker candidates under investigation for irAE diagnosis and prediction include blood cell analysis, chemokines/cytokines, autoantibodies, and genetic predisposition, such as human leukocyte antigen haplotype. Among other emerging candidates are immune-cell subsets, T-cell repertoire, fecal microbiome, tumor genomics, and radiomic characterization.

Summary: Several conventional laboratory indexes of end-organ dysfunction are currently in routine clinical use for irAE monitoring and diagnosis. Novel biomarkers for the prediction and diagnosis of these irAEs, which primarily characterize patient immune function, represent an area of active investigation.

Fig. 1.

Mechanisms underlying irAEs. Schematic representation of potential mechanisms underlying irAEs associated with ICI therapy. CTLA-4 expression on regulatory T cells is critical in maintaining peripheral tolerance by preventing activation of self-reactive T cells. CTLA-4 blockade may result in depletion of Tregs, may alter Treg function, and may modulate T-cell repertoire, resulting in autoreactive T cells that can, in turn, affect B-cell function and increased autoantibody production (A). PD-1- and CTLA-4-mediated negative regulation of T cells is critical in maintaining self-tolerance via suppressing costimulation. PD-1 and CTLA-4 blockade results in enhanced effector function of T cells and may lead to generation of pathogenic T cells, overproduction of cytokines, alteration of B cell numbers/function and increased production of autoantibodies leading to inflammation and autoimmunity (B). PD-1 blockade may result in reactivation of exhausted/anergic T cells resulting in pathogenic/self-reactive T cells (C). Epitope spreading can lead to breakdown of tolerance. Tumor cell death results in production of self and tumor antigens that are ingested by APCs, which migrate to lymph nodes and prime T cells. These self-reactive T cells can reenter normal tissues, recognize self-antigens, and result in increased cytokine production and autoantibodies leading to breakdown of tolerance and tissue destruction (D). ICI therapy may directly result in breakdown of tolerance in organs via binding to CTLA-4 expressed on normal tissues (E); production of de novo autoantibodies and/or increased levels of preexisting autoantibodies (F); and increased levels of pro inflammatory cytokines locally, leading to infiltration of pathogenic immune cells (G). These factors can generate a local inflammatory milieu resulting in organ damage. APC, antigen-presenting cell; MHC, major histocompatibility complex; Treg, regulatory T cell; TCR, T-cell receptor.