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Immune-related adverse events with immune checkpoint inhibitors: Special reference to the effects on the lungs.

ABSTRACT:

Abstract

Immune checkpoint inhibitors (ICIs) have emerged as evolutionary treatments for malignant diseases. Although ICIs can cause immune-related adverse events (irAEs) in various organs, precise timing after ICI initiation has been scarcely reported. Elucidating the effects of irAEs, such as time to onset, involvement of major organs, influence on progression-free survival (PFS), and overall survival (OS), are critical issues for physicians. Furthermore, lung-irAE as a whole is not well known.We conducted a retrospective study of 156 patients who were treated with ICIs and compared 82 irAE patients with 74 non-irAE patients.This study clearly demonstrated that the preferred period after induction of ICIs was significantly longer in lung-irAE than in other major organs (skin, digestive tract, and endocrine). The effect of irAEs on PFS and OS was evident PFS in the irAE group (n = 82) (median 128 days, interquartile range [IQR] 62-269 days, P = .002) was significantly longer than that in the non-irAE group (n = 74) (median 53 days, IQR 33-151 days). Similarly, OS was significantly longer in the irAE group (median 578 days, IQR 274-1027 days, P = .007) than in the non-irAE group (median 464 days, IQR: 209-842 days). However, this positive effect of irAEs in the lungs was not proportional to the extent of severity.Lung-irAEs can occur at a later phase than non-lung-irAEs and seemed not to prolong OS and PFS. However, further studies are needed to support these findings.

SUBMITTER: Hirata A

PROVIDER: S-EPMC8036099 | 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.

Project description:Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies.

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Immune-related adverse events with immune checkpoint inhibitors: Special reference to the effects on the lungs.

Abstract

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