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Predictive Biomarkers of Severe Immune-Related Adverse Events With Immune Checkpoint Inhibitors: Prevention, Underlying Causes, Intensity, and Consequences.

ABSTRACT: Immune checkpoint inhibitors (ICIs) have dramatically transformed oncology by prolonging overall survival and yielding better patient tolerance compared to other chemotherapeutic agents. However, numerous questions remain unanswered about the toxicity profile of ICIs, its relationship with the treatment response, and causes underlying the excellent treatment response in some patients, while recalcitrance in others. Research groups have continued to seek biomarkers that may permit the identification of treatment responders and predict toxicity to facilitate cessation of immunotherapy before the development of severe toxicity. However, some studies have found associations between serious adverse events and longer survivorship. The research question entailed determining whether a biomarker is needed to predict severe immune-related adverse events prior to their development or whether providing early treatment for toxicity would inhibit the immune system from attaining a long-lasting anti-tumor effect. Therefore, this review conducted an in-depth analysis into the molecular basis of these observations.

SUBMITTER: Cardena-Gutierrez A

PROVIDER: S-EPMC9237384 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Although immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with many advanced malignancies, only 15-60% of patients respond, leaving a broad swath of patients who do not derive benefit. Identifying biomarkers to optimally identify patients who will benefit from ICIs is a major research focus for the oncology community. Thus far, predictive biomarker research has focused on tumor signatures such as microsatellite instability, programmed death-ligand 1 (PD-L1) expression and tumor mutational burden; clinical biomarkers have been far less studied. One potential clinical biomarker for ICI response in patients is immune-related adverse event (IRAE) onset.IRAEs are thought to represent bystander effects from activated T-cells and it is plausible that patients responding to ICIs would have greater likelihood of autoimmune toxicities (e.g. due to a more competent/treatment-responsive immune system, or cross-reactivity between tumor and host tissue). Earlier studies in melanoma patients however, suggested no association between IRAE onset and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody efficacy. In contrast, a growing body of literature suggests IRAE onset is predictive of anti-programmed cell death protein 1 (PD-1) and anti-PD-L1 antibody response across a variety of solid tumors. Most of these studies report that patients who experienced IRAEs demonstrate marked improvements in progression-free survival, overall survival and overall response rate compared to those lacking toxicity.Key questions regarding the association between IRAE onset and ICI efficacy remain. The most pertinent of these involve whether the association is only relevant for patients treated with anti-PD-1 and anti-PD-L1 antibodies and whether IRAE site, severity, timing of onset and management influence ICI efficacy. Herein, we discuss the seminal studies which have begun to address these questions and have shaped the narrative about the predictive value of IRAE onset for patients on ICIs, in this review.

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Predictive Biomarkers of Severe Immune-Related Adverse Events With Immune Checkpoint Inhibitors: Prevention, Underlying Causes, Intensity, and Consequences.

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