scholarly journals The Role of Cytokines in Predicting the Response and Adverse Events Related to Immune Checkpoint Inhibitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Wang ◽  
Xiaoyang Zhai ◽  
Ji Li ◽  
Jingyuan Guan ◽  
Shuhui Xu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Tnf Α ◽  
Wide Range

Recently, the overall survival (OS) and progression-free survival (PFS) of patients with advanced cancer has been significantly improved due to the application of immune checkpoint inhibitors (ICIs). Low response rate and high occurrence of immune-related adverse events (irAEs) make urgently need for ideal predictive biomarkers to identity efficient population and guide treatment strategies. Cytokines are small soluble proteins with a wide range of biological activity that are secreted by activated immune cells or tumor cells and act as a bridge between innate immunity, infection, inflammation and cancer. Cytokines can be detected in peripheral blood and suitable for dynamic detection. During the era of ICIs, many studies investigated the role of cytokines in prediction of the efficiency and toxicity of ICIs. Herein, we review the relevant studies on TNF-α, IFN-γ, IL-6, IL-8, TGF-β and other cytokines as biomarkers for predicting ICI-related reactions and adverse events, and explore the immunomodulatory mechanisms. Finally, the most important purpose of this review is to help identify predictors of ICI to screen patients who are most likely to benefit from immunotherapy.

Behcet’s-like syndrome following pembrolizumab: An immune-related adverse event associated with programmed death receptor-1 inhibitor therapy

2019 ◽  
Vol 26 (4) ◽  
pp. 995-999 ◽  
Author(s):  
Steffi Thomas ◽  
Chay Bae ◽  
Tabanor Joy-Ann ◽  
William Traverse
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Programmed Death ◽  
Organ Systems ◽  
Wide Range ◽  
The Right

Introduction The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system. Case report We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations. Management and outcome Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer. Discussion Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet’s disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet’s-like syndrome presentation.

scholarly journals Role of Immune Checkpoint Inhibitors in Gastrointestinal Malignancies

2020 ◽  
Vol 9 (8) ◽  
pp. 2533
Author(s):  
Anita Mazloom ◽  
Nima Ghalehsari ◽  
Victor Gazivoda ◽  
Neil Nimkar ◽  
Sonal Paul ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Small Subset ◽  
Gastrointestinal Malignancies ◽  
Line Of Therapy

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several solid and hematological malignancies. ICIs are not only able to produce long and durable responses, but also very well tolerated by patients. There are several approved indications of use of ICIs in treatment of metastatic gastrointestinal malignancies including gastric, esophageal, colorectal and hepatocellular carcinoma. In addition, ICIs can be used in microsatellite instability-high (MSI-H) and high tumor mutational burden (TMB) tumors in chemotherapy-resistant setting. Despite having good efficacy and superior safety profile, ICIs are clinically active in small subset of patients, therefore, there is a huge unmet need to enhance their efficacy and discover new predictive biomarkers. There are several ongoing clinical trials that are exploring the role of ICIs in various gastrointestinal cancers either as single agent or in combination with chemotherapy, radiation therapy, targeted agents or other immunotherapeutic agents. In this review, we discuss the published and ongoing trials for ICIs in gastrointestinal malignancies, including esophageal, gastric cancer, pancreatic, hepatocellular, biliary tract, colorectal and anal cancers. Specifically, we focus on the use of ICIs in each line of therapy and discuss the future directions of these agents in each type of gastrointestinal cancer.

scholarly journals Immune checkpoint inhibitors, endocrine adverse events, and outcomes of melanoma

2022 ◽  
Author(s):  
Hanna Karhapää ◽  
Siru Mäkelä ◽  
Hanna Laurén ◽  
Marjut Jaakkola ◽  
Camilla Schalin-Jäntti ◽  
...  
Keyword(s):  
Adverse Events ◽  
Treatment Outcomes ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Autoimmune Diabetes ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Melanoma Patients

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients. Design: A retrospective single-institution study. Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed endocrine toxicity and best possible treatment outcomes from electronic patient records, including laboratory parameters, and radiological images. Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and six (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1 – 11.1 months vs. 2.7 months, range 2.4 – 3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5 – 79.5 months vs. 23.7 months, range 15.3 – 32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs. Conclusions: The higher number of endocrine AEs suggest regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.

scholarly journals Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 271
Author(s):  
Francesca Comito ◽  
Rachele Pagani ◽  
Giada Grilli ◽  
Francesca Sperandi ◽  
Andrea Ardizzoni ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Cutaneous Melanoma ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Biological Effects ◽  
Adoptive Cell Therapy ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Area Of Interest

The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies.

Immunological and clinical profiles of patients with advanced or metastatic melanoma receiving immune checkpoint inhibitors to investigate potential biomarkers for immune-related adverse events.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14037-e14037
Author(s):  
Stephanie A. Berg ◽  
Michael Wesolowski ◽  
Brianna Burke ◽  
Courtney Regan Wagner ◽  
Joseph I Clark ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Rank Correlation ◽  
Predictive Biomarkers ◽  
Biological Variables

e14037 Background: Immune-related adverse events (irAEs) related to immune checkpoint inhibitors (ICIs) may target any organ and originate from autoreactive T cells injuring host tissues. There is a need to develop prognostic and predictive biomarkers to distinguish patients (pts) who will benefit from ICIs avoiding irAEs during treatment. We propose that irAEs are the result of many biological variables. We hypothesize that within each pts complex immunological profile, there may be patterns and associations which exist that represent a state of inflammation that is present prior to ICI therapy and hypothesize this could predict irAEs development. Methods: We created individual immunological profiles of 11 pts diagnosed with MM prior to receiving ICIs. Assays included: PBMC composition, circulating chemokines/cytokines, and IκB degradation status. CD4 and CD8 T cells were studied for their phenotype, activation status, proliferative capacity and cytolytic granules. Clinical data was collected on a larger MM pt cohort (n = 41) and descriptive statistics were utilized to characterize reported irAEs . Results: 110 input markers were utilized for immune signature analysis. 6 of the 11 pts reported grade 2+ irAEs after ICI therapy. The pro-inflammatory CCL13, CCL1, FLT-3, IL12p40, TRAIL, and granzyme b expressing CD4 T cells at steady state and after CD3 activation were significantly higher in pts with irAEs. Known inflammatory suspects (i.e., IL-2, IL-15, TNF-a or % CD8 T cells) were not associated with irAE development . A rank correlation test showed significant associations between the levels of these factors. irAEs were reported in 41% (n = 17) for our larger cohort, most frequently skin rash (7%), colitis (7%), hepatitis (7%) and thyroid dysfunction (4%). Conclusions: The immune signatures of pts with irAEs are highly heterogeneous and possess distinctive immunological patterns. Our results introduce possible molecular mechanisms that may aid understanding of irAE development, perhaps providing the basis for a new model prospectively testing these markers to risk stratify pts receiving ICIs.

scholarly journals Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?

2019 ◽  
Vol 11 ◽  
pp. 175883591986190 ◽  
Author(s):  
Giandomenico Roviello ◽  
Silvia Paola Corona ◽  
Gabriella Nesi ◽  
Enrico Mini
Keyword(s):  
Overall Survival ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
First Line

Background: The aim of this study was to perform a literature-based meta-analysis to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in first-line metastatic renal cell carcinoma (RCC), focusing on the predictive role of PD-L1 expression. Methods: The primary outcome was overall survival, and secondary outcomes were progression-free survival (PFS) and objective response. We planned a subgroup analysis for overall survival according to PD-L1 status. Results: Five studies were included in the analysis for a total of 4063 cases. Overall survival was greater in PD-L1 positive tumours (HR = 0.49, 95% CI: 0.36–0.67; p < 0.001). The pooled analysis of the unselected cases showed a statistically significative improvement in PFS with the use of ICIs (HR = 0.85, 95% CI: 0.72–0.99; p = 0.04) and we found a greater PFS benefit (HR = 0.65, 95% CI: 0.57–0.74; p < 0.001) in patients with PD-L1 positive tumours. Conclusions: This study supports the efficacy of ICIs and, although a significant clinical benefit has been reported in PD-L1 negative patients, a greater efficacy of ICIs was observed in PD-L1 positive patients. More prospective randomized studies are needed to clarify the role of PDL-1 status in metastatic RCC treated with ICIs.

Assessment of hospitalization rates for immune-related adverse events with immune checkpoint inhibitors

2020 ◽  
pp. 107815522096890
Author(s):  
Laura Nice ◽  
Ryan Bycroft ◽  
Xiaoyong Wu ◽  
Shesh N Rai ◽  
Lindsay Figg ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Median Length ◽  
Number Of Patients ◽  
Grade 3 ◽  
The Impact

Introduction Immune checkpoint inhibitors (ICIs) have become the standard of care in many cancer types. As the number of patients receiving ICIs for various cancers continues to expand, patients and practitioners should be aware of potentially severe immune-related adverse events (irAEs). Despite reports of the incidence of grade 3/4 toxicities, the proportion of patients whose symptoms were clinically severe enough to warrant hospitalization for adverse event management is unknown. Methods This single center, retrospective, observational study was designed to determine the impact of irAEs on patients and the hospital. Patients who started ICIs from May 2016 through May 2019 for melanoma or lung cancer were included. The primary outcome was incidence of hospitalization for irAE. Secondary outcomes included median length of hospitalization, time to onset of irAE, rates of hospitalization for irAE per each checkpoint inhibitor regimen, organ system affected, progression free survival, and overall survival. Results Of 384 patients with melanoma or lung cancer, 27 (7%) were hospitalized at our institution for an irAE. The most common irAE leading to hospitalization was colitis for patients with melanoma and pneumonitis for patients with lung cancer. The median length of stay across all hospitalizations was 10 days. Twenty-five patients required the use of corticosteroids while hospitalized, while eight of these patients required second line irAE treatment. For the total patient population, 34.7% experienced a grade 1/2 irAE and 13.1% experienced a grade 3/4 irAE. Conclusion Our cohort of patients experienced similar rates irAEs as reported in clinical trials and published reports.

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