scholarly journals Resistance to immune checkpoint inhibitors in advanced gastro-oesophageal cancers

2021 ◽  
Author(s):  
Mark A. Baxter ◽  
Fearghas Middleton ◽  
Hannah P. Cagney ◽  
Russell D. Petty
Keyword(s):  
Oesophageal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Patient Specific ◽  
Cancer Type ◽  
Early Stage Disease ◽  
Treatment Paradigm ◽  
Research Challenge

AbstractImmune checkpoint inhibitors (ICIs) have altered the treatment paradigm across a range of tumour types, including gastro-oesophageal cancers. For patients with any cancer type who respond, ICIs can confer long-term disease control and significantly improve survival and quality of life, but for patients with gastro-oesophageal cancer, ICIs can be transformative, as durable responses in advanced disease have hitherto been rare, especially in those patients who are resistant to first-line cytotoxic therapies. Results from trials in patients with advanced-stage gastro-oesophageal cancer have raised hopes that ICIs will be successful as adjuvant and neoadjuvant treatments in early-stage disease, when the majority of patients relapse after potential curative treatments, and several trials are ongoing. Unfortunately, however, ICI-responding patients appear to constitute a minority subgroup within gastro-oesophageal cancer, and resistance to ICI therapy (whether primary or acquired) is common. Understanding the biological mechanisms of ICI resistance is a current major research challenge and involves investigation of both tumour and patient-specific factors. In this review, we discuss the mechanisms underlying ICI resistance and their potential specific applications of this knowledge towards precision medicine strategies in the management of gastro-oesophageal cancers in clinical practice.

scholarly journals Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

2020 ◽  
Vol 22 (1) ◽  
pp. 190
Author(s):  
Fulvio Borella ◽  
Mario Preti ◽  
Luca Bertero ◽  
Giammarco Collemi ◽  
Isabella Castellano ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
State Of The Art ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Survival Rates ◽  
Younger Women ◽  
Multiple Tumor ◽  
Tumor Types

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

Updates in the management and future landscape of urothelial carcinoma

2020 ◽  
pp. 107815522097102
Author(s):  
Kirollos S Hanna ◽  
Maren Campbell ◽  
Adam Kolling ◽  
Alex Husak ◽  
Sabrina Sturm ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Urothelial Carcinoma ◽  
Metastatic Disease ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Locally Advanced ◽  
The United States ◽  
Cancer Type ◽  
Antibody Drug Conjugate ◽  
Early Stage Disease

Urothelial carcinoma is the sixth most common cancer type in the United States. Although most patients present with early stage disease which is associated with improved outcomes, many will progress to locally advanced or metastatic disease. Immune checkpoint inhibitors have significantly impacted the treatment paradigm for patients and have resulted in improved survival rates. Despite their proven efficacy, many ongoing clinical trials continue to refine combinations with chemotherapy, sequencing of therapies and the role of ligand expression. Additionally, novel targets have been identified for advanced urothelial carcinoma and have led to the approval of the antibody-drug conjugate, enfortumab vedotin, and the fibroblast growth factor receptor-targeted, erdafitinib. Enrollment in a clinical trial is strongly encouraged for all stages of advanced or metastatic disease. Numerous ongoing clinical trials are likely to impact the treatment armamentarium for patients. In this manuscript, we highlight key updates in the clinical management for patients and outline ongoing trials.

A Career in Lung Cancer: Pushing Beyond Chemotherapy

2019 ◽  
pp. 583-589
Author(s):  
Pradnya Dinkar Patil ◽  
Frances Shepherd ◽  
David H. Johnson
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Genetic Alterations ◽  
Disease Biology ◽  
Formidable Challenge ◽  
Treatment Paradigm

The landscape of treatments for non–small cell lung cancer (NSCLC) has evolved dramatically over the past 3 decades. A better understanding of the disease biology and identification of actionable genetic alterations heralded an era of targeted therapies that has led to unprecedented survival benefits in patients with oncogene-driven NSCLC. More recent breakthroughs in immunotherapy led to the development of immune checkpoint inhibitors that have changed the treatment paradigm for patients with advanced NSCLC because of their ability to produce durable responses, resulting in improved survival outcomes. Despite the unparalleled success of these agents, primary and acquired resistance to these therapies pose a formidable challenge. In this article, we provide an overview of the therapeutic advances in the treatment of NSCLC, mechanisms of resistance, and potential strategies to overcome resistance to targeted therapies and immune checkpoint inhibitors.

scholarly journals Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges

2020 ◽  
Vol 21 (2) ◽  
pp. 597 ◽  
Author(s):  
Kei Kunimasa ◽  
Taichiro Goto
Keyword(s):  
Lung Cancer ◽  
Immune System ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Evolution ◽  
Clinical Activity ◽  
Cancer Immunoediting ◽  
Treatment Paradigm ◽  
Nsclc Patients

The immune system plays a dual role in tumor evolution—it can identify and control nascent tumor cells in a process called immunosurveillance and can promote tumor progression through immunosuppression via various mechanisms. Thus, bilateral host-protective and tumor-promoting actions of immunity are integrated as cancer immunoediting. In this decade, immune checkpoint inhibitors, specifically programmed cell death 1 (PD-1) pathway inhibitors, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). These agents are approved for the treatment of patients with NSCLC and demonstrate impressive clinical activity and durable responses in some patients. However, for many NSCLC patients, the efficacy of immune checkpoint inhibitors is limited. To optimize the full utility of the immune system for eradicating cancer, a broader understanding of cancer immunosurveillance and immunoediting is essential. In this review, we discuss the fundamental knowledge of the phenomena and provide an overview of the next-generation immunotherapies in the pipeline.

scholarly journals Frequency and distribution of various rheumatic disorders associated with checkpoint inhibitor therapy

Rheumatology ◽  
2019 ◽  
Vol 58 (Supplement_7) ◽  
pp. vii40-vii48 ◽  
Author(s):  
Noha Abdel-Wahab ◽  
Maria E Suarez-Almazor
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Incidence Rates ◽  
Cancer Therapies ◽  
True Incidence ◽  
Immune System Activation ◽  
Treatment Paradigm ◽  
Checkpoint Inhibitor Therapy ◽  
Prospective Longitudinal

Abstract Immune checkpoint inhibitors have advanced the treatment paradigm of various cancers, achieving remarkable survival benefits. However, a myriad of immune-related adverse events (irAE) has been recognized in almost every organ system, presumably because of persistent immune system activation. Rheumatic symptoms such as arthralgia or myalgia are very common. More specific irAE are increasingly being reported. The most frequent ones are inflammatory arthritis, polymyalgia-like syndromes, myositis and sicca manifestations. These rheumatic irAE can develop in ∼5–10% of patients treated with immune checkpoint inhibitors, although true incidence rates cannot be estimated given the lack of prospective cohort studies, and likely underreporting of rheumatic irAE in oncology trials. In this review, we will provide a summary of the epidemiologic data reported for these rheumatic irAE, until more robust prospective longitudinal studies become available to further define the true incidence rate of rheumatic irAE in patients receiving these novel cancer therapies.

Effect of antibiotic use prior to or concurrent with immune checkpoint inhibitors on outcomes in patients with Hodgkin lymphoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8030-8030
Author(s):  
Steven R Hwang ◽  
Alexandra Higgins ◽  
Betsy LaPlant ◽  
Matthew J. Maurer ◽  
Stephen M. Ansell ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cox Regression ◽  
Checkpoint Inhibitors ◽  
Retrospective Chart Review ◽  
Progression Free Survival ◽  
Antibiotic Use ◽  
Patient Specific ◽  
Cox Regression Analysis

8030 Background: There is growing interest in the identification of modifiable patient-specific factors that may predict response to immune checkpoint inhibitors (ICIs) in classical Hodgkin lymphoma (cHL). Recently, it has been proposed that antibiotic use could decrease the efficacy of ICIs in the treatment of advanced solid malignancies. The objective of our study is to assess whether antibiotic use prior to or concurrent with ICIs is associated with changes in outcomes in patients with cHL. Methods: Patients who received a PD-1 or CTLA-4 blocker for the treatment of cHL at Mayo Clinic Rochester between January 1, 2011 and October 20, 2018 were identified. We conducted a longitudinal retrospective chart review to identify those who received antibiotics within 30 or 90 days prior to initiation or concurrent with ICI therapy. Univariate cox regression analysis was used to assess for an association between antibiotic use and overall survival (OS) and progression-free survival (PFS) within these groups; a time-dependent variable was used for concurrent antibiotic use. Results: A total of sixty-two patients were identified (61% male, median age at ICI initiation 35 years [range: 19-87]). Median duration of follow up from ICI start was 38 months (range: 4-78). Twenty-one patients (34%) received antibiotics within 90 days of initiation of ICI, of which thirteen (21%) received antibiotics within 30 days. Thirty-five patients (57%) received antibiotics concurrently with ICI. Concurrent and prior antibiotic use within 90 days of ICI were both associated with inferior PFS (concurrent HR = 6.38 [95% CI 3.02-13.47]; 90-day HR = 2.21 [95% CI 1.10-4.47]) and OS (concurrent HR = 8.77 [95% CI 1.91-40.36]; 90-day HR = 2.96 [95% CI 1.09-8.04]). Conclusions: Antibiotic use is associated with inferior outcomes in patients with cHL treated with ICIs in this single institution cohort. This may reflect potential antibiotic effects on the gut microbiome (GMB) and immune system as has been suggested in prior studies. Further confirmatory studies and examination of potential confounding covariates are needed.

Risk factors for myocarditis associated with immune checkpoint inhibitors using real-world clinical data.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15100-e15100 ◽  
Author(s):  
Prantesh Jain ◽  
Jahir Gutierrez Bugarin ◽  
Avirup Guha ◽  
Chhavi Jain ◽  
Tingke Shen ◽  
...  
Keyword(s):  
Risk Factors ◽  
Liver Disease ◽  
Cancer Patients ◽  
Real World ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cox Proportional Hazards ◽  
Cancer Type ◽  
Real World Data

e15100 Background: Immune checkpoint inhibitors (ICIs) can cause unique, high-grade immune-related adverse events. Although rare, ICI related myocarditis has the highest fatality rate (~50%). Cardiovascular monitoring is not routinely performed in patients on ICI treatment, thus risk factors remain unknown. Characterizing rare but fatal cardiac toxicities requires integration of real-world data. Methods: U.S claims data (IBM MarketScan) of over 30 million commercially insured individuals was leveraged to identify 2,687,301 cancer patients between 2011-2018. Patients ≥18 years of age treated with ICIs (targeting CTLA4 (ipilimumab) and/or the PD1 (nivolumab, pembrolizumab)/PDL1 (atezolizumab, avelumab, durvalumab) alone or in combination with ICI and/or chemotherapy were identified and followed until disenrollment. Myocarditis, comorbidities, and treatment details were identified using diagnosis and billing codes. Analyses included descriptive statistics and Cox proportional hazards regression. Results: 16,541 ICI treated cancer patients were included (median age 60; 58% male). Myocarditis was identified in 252 (1.5%) patients, majority (90%) ≥50 years old (median 63) with 12,040 person-years of follow up. 62% received anti-PD1 monotherapy, 12% anti-CTLA4, and 15% received combination treatment with other ICIs and/or chemotherapy. Most common cancer types were lung (48%), melanoma (25%), and renal cancer (14%). Cumulative incidence of myocarditis at 1 year was 2.06%; 95% CI (1.78-2.37), median onset of 80.5 days, 42% occurring within 60 days of treatment. By univariate analyses, age, cancer type, diabetes (DM), hypertension (HTN), kidney, liver disease, atrial fibrillation (AF) were related to myocarditis. Risk was lower in patients who received anti-CTLA4 monotherapy (HR: 0.490; 95% CI: 0.26-0.92; p = 0.0251). On multivariable regression analyses only age, cancer type (renal, lung cancer), comorbidities DM and liver disease were significantly associated with myocarditis (Table). Conclusions: This is the largest real-world longitudinal study for ICI associated myocarditis showing higher than reported incidence and identifiable risk factors. [Table: see text]

Markers of immune checkpoint inhibitor efficacy in the AACR Project GENIE database.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15091-e15091
Author(s):  
Yuanchu J Yang ◽  
Sam Rubinstein ◽  
Jeremy Lyle Warner
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Metastatic Breast ◽  
Copy Number Gain ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Reference Allele ◽  
Resected Nsclc ◽  
Tumor Types

e15091 Background: Although immune checkpoint inhibitors (ICIs) have been shown to be effective in many tumor types, some highly lethal cancers are not responsive to ICI. Potential biomarkers of ICI response include tumor mutational burden (TMB), which is thought to correlate with increased neoantigen production, and 9p24.1 copy number gain (CNG), which can result in over-expression of programmed death ligand 1 (PD-L1). 9p24.1 CNGs have been described in ICI-sensitive (ICI-S) hematologic malignancies (e.g., Hodgkin lymphoma), but are not well described in solid malignancy. We sought to investigate TMB and 9p24.1 CNG for ICI-S and ICI-resistant (ICI-R) tumor types in the publicly available AACR Project GENIE database, version 7.0. Methods: TMB was calculated by counting somatic mutations with tumor reference allele frequency ≥5% and sequencing depth ≥200X. Samples with < 0.5 MB sequenced were excluded. 9p24.1 CNG was extrapolated from gene-level data. Samples with two or more consecutive gene amplifications in the 9p24.1 region were determined to have 9p24.1 CNG. Samples whose sequencing assay did not include at least two genes in 9p24.1 were excluded. Using an overall response rate (ORR) of ≥10% to define ICI-S, we assessed three ICI-S cancers: hepatobiliary cancer (HBC), melanoma (MEL), non-small cell lung cancer (NSCLC); and two ICI-R types: metastatic breast cancer (MBC) & pancreatic ductal adenocarcinoma (PDAC). Groupwise TMB was compared using Wilcoxon rank-sum and 9p24.1 CNG was compared using Chi-squared. Results: MEL had the highest median TMB but a low 9p24.1 CNG rate; NSCLC had the highest rate of 9p24.1 CNG (Table). PDAC had both the lowest median TMB and 9p24.1 CNG rate. As a group, the ICI-S cancers had higher median TMB (p < .001) and 9p24.1 CNG rate (p < .001). Conclusions: Although rates of 9p24.1 CNG were low across the database as a whole, the NSCLC finding replicates findings described in early stage resected NSCLC (Inoue et al. 2016). Relatively high median TMB in MEL may explain ICI-sensitivity in this cancer type. The combination of low median TMB and low rates of 9p24.1 CNG in PDAC may explain the general lack of efficacy of ICIs in this disease. These findings demonstrate the utility of GENIE as a clinico-genomic database, and also highlight the need to identify better markers of responsiveness to these potentially effective but toxic therapies. [Table: see text]

scholarly journals Case Report: Cardiac Toxicity Associated With Immune Checkpoint Inhibitors

2021 ◽  
Vol 8 ◽  
Author(s):  
Ru Chen ◽  
Ling Peng ◽  
Zhihua Qiu ◽  
Yan Wang ◽  
Fen Wei ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Troponin I ◽  
Systemic Corticosteroid ◽  
Checkpoint Inhibitors ◽  
Cardiac Conduction ◽  
Fulminant Myocarditis ◽  
Cancer Type ◽  
Life Threatening ◽  
The Subject

Immune checkpoint inhibitors (ICIs) have now emerged as a mainstay of treatment for various cancer. Along with the development of ICIs, immune-related adverse effects (irAEs) have been the subject of wide attention. The cardiac irAE, a rare but potentially fatal and fulminant effect, have been reported recently. This article retrospectively reviewed 10 cases from our hospital with cardiac irAEs, with severity ranging from asymptomatic troponin-I elevations to cardiac conduction abnormalities and even fulminant myocarditis. In our series, all the cases were solid tumors and lung cancer was the most frequent cancer type (4,40%). In total, three (30.0%) patients experienced more than one type of life-threatening complication. A systemic corticosteroid was given to nine patients (90.0%). The majority of cases (7, 70%) were performed at an initial dose of 1–2 mg/kg/day. Two (20.0%) patients were admitted to ICU, three (30.0%) patients were put on mechanical ventilation, two (20.0%) patients received the plasma exchange therapy, and one patient was implanted with a pacemaker. Two (20.0%) of the patients succumbed and died, with a median duration of 7.5 days (IQR5.0–10.0) from diagnosis of cardiac irAE to death. Based on these results, we recommend that clinicians be alert to cardiac irAEs, including performing cardiovascular examinations before ICI treatment to accurately diagnose suspected myocarditis, enabling immediate initiation of immunosuppressive therapy to improve prognosis.

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