Gastrointestinal and Hepatic Toxicities of Checkpoint Inhibitors: Algorithms for Management

2018 ◽  
pp. 13-19 ◽  
Author(s):  
Shilpa Grover ◽  
Osama E. Rahma ◽  
Nikroo Hashemi ◽  
Ramona M. Lim
Keyword(s):  
Adverse Effects ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Effective Management ◽  
Rule Out

Gastrointestinal toxicities are among the leading causes of immune-related adverse effects of checkpoint blockade. These adverse events can be severe enough to require interruption or withdrawal of immune checkpoint blockade therapy. Patients with immune-related adverse effects require early recognition with an evaluation to rule out alternative etiologies and effective management to minimize complications. This article reviews the gastrointestinal and hepatic toxicities of the antibodies that target immune checkpoints CTLA-4 and PD-1/PD-L1 and provides an approach to their diagnosis and management.

Dermatologic adverse events with immune checkpoint blockade: Systematic review and meta-analysis.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 84-84
Author(s):  
Kushal Naha ◽  
Lakshmi Manogna Chintalacheruvu ◽  
Donald C. Doll ◽  
Sowjanya Naha
Keyword(s):  
Adverse Effects ◽  
Adverse Events ◽  
Confidence Interval ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Randomized Controlled ◽  
Dermatologic Adverse Events

84 Background: Immune checkpoint blockade is known to be associated with various dermatologic adverse events. However, these adverse effects have not been studied in a systematic manner. This is especially relevant considering the rapidly increasing number of immune checkpoint inhibitors that are now available. Methods: We searched for eligible studies in PubMed and Google scholar. We reviewed randomized controlled trials involving cancer patients treated with immune checkpoint inhibitors - PD1 inhibitors, PDL1 inhibitors and CTLA4 inhibitors and for dermatologic adverse effects. A total of 47 randomized controlled trials involving 11875 patients met eligibility criteria for our study. Results: Incidence rate of all grade dermatologic adverse effects was 40.6% (95% confidence interval [CI], 39.4-41.7%). Most common adverse effects included pruritus (17.3%) (95% confidence interval [CI] 16.6-18.1%), undifferentiated rash (15.1%) (95% confidence interval [CI] 14.4-15.9%), vitiligo (3.6%) (95% confidence interval [CI] 3.2-3.9%), maculopapular rash (2.3%) (95% confidence interval [CI] 2.1-2.6%), stomatitis (0.7%) (95% confidence interval [CI] 0.55-0.92%) and dry skin (0.7%) (95% confidence interval [CI] 0.5-0.8%). Less common adverse events include palmoplantar erythrodysesthesia, pemphigoid skin reactions, lichen planus and hyperhidrosis. Grade 3 and higher adverse effects were seen in 1.3% of patients (95% confidence interval [CI] 1.1-1.6%). Conclusions: A wide range of dermatologic adverse effects can be seen with immune checkpoint blockade. While the majority of these events are of grade 1-2, they can occasionally be severe and even life threatening. Patients receiving immune checkpoint blockade should be closely monitored for dermatologic adverse effects.

scholarly journals Overview of Immune Checkpoint Inhibitors Therapy for Hepatocellular Carcinoma, and The ITA.LI.CA Cohort Derived Estimate of Amenability Rate to Immune Checkpoint Inhibitors in Clinical Practice

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1689 ◽  
Author(s):  
Edoardo Giannini ◽  
Andrea Aglitti ◽  
Mauro Borzio ◽  
Martina Gambato ◽  
Maria Guarino ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Practice ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Critical Evaluation ◽  
Real Life ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints

Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC.

scholarly journals Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response

2020 ◽  
Vol 9 (1) ◽  
pp. 286 ◽  
Author(s):  
Qingyang Xiao ◽  
André Nobre ◽  
Pilar Piñeiro ◽  
Miguel-Ángel Berciano-Guerrero ◽  
Emilio Alba ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Current Status ◽  
Immune Checkpoints ◽  
Current Response ◽  
Epigenetic Biomarkers

Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.

Cutaneous adverse events associated with immune checkpoint blockade: A meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14500-e14500
Author(s):  
Yiqun Han ◽  
Jiayu Wang ◽  
Binghe Xu
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Meta Analysis ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Cochrane Library ◽  
Predictive Values ◽  
Dermatological Toxicity

e14500 Background: Dermatological toxicity is the most common immune-related adverse events (irAEs) following immune checkpoint inhibitors (ICIs). A better understanding of this side effect enables early recognition, diagnosis, and management in clinical practice. Methods: We did a meta-analysis of literature published on ClinialTrials.gov, Pubmed, Embase, and Cochrane Library up to April 30, 2020. Randomized controlled trials (RCTs) which reported the cases of cutaneous irAEs following ICIs (anti-PD-1, anti-PD-L1, anti-CTLA-4) were included. We comprehensively assessed the differences in cutaneous irAEs among ICIs, the effect from dosage and combined treatment on the incidence, the correlations of cutaneous irAE with other organ-specific irAEs, and the predictive values for prognosis. This study was prospectively registered in the PROSPERO platform (ID: CRD42020182247). Results: A total of 687 publications were initially identified and 46 eligible RCTs involving 28569 patients were included. Compared with that in patients receiving anti-CLTA-4 antibody, the overall risk of dermatological irAEs tended to be lower in patients receiving anti-PD-1 antibody (RRrash, 0.60; 95%CrI, 0.36-0.99; RRpruritus, 0.51; 95%CrI, 0.22-1.10) and was lower in those receiving anti-PD-L1 antibody (RRrash, 0.63; 95%CrI, 0.43-0.90; RRpruritus, 0.37; 95%CrI, 0.20-0.67). In general, neither treatment in combination nor dosage were estimated to add additional risk to the incidence of cutaneous irAEs. Dermatological toxicity was positively associated with immune-related hepatitis (P = 0.006), neuropathy (P = 0.040) and gastrointestinal dysfunctions (P = 0.038). The cutaneous irAEs was not confirmed as a surrogate predictor for survival with ICIs monotherapy. Conclusions: This study indicates that cutaneous irAEs are dose-independent and agent-specific immune reactions with the highest risk observed in CTLA-4 blockade, and the occurrence is associated with hepatic, neurological, and gastrointestinal disorders. The exploration in the predictive value of cutaneous irAEs for response and survival outcomes will be warranted in the future.

scholarly journals Cutaneous Adverse Events of Immune Checkpoint Inhibitors: A Literature Review

2021 ◽  
pp. e2021155
Author(s):  
Zoe Apalla ◽  
Chryssoula Papageorgiou ◽  
Aimilios Lallas ◽  
Florentina Delli ◽  
Christina Fotiadou ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Skin Toxicity ◽  
Immune Checkpoint Blockade ◽  
Self Tolerance ◽  
Oncologic Patients ◽  
Dose Modifications

Immune checkpoint inhibitors (CPIs) are targeted molecules that modulate the immune system, assist with self-tolerance, and minimize collateral tissue damage when immune responses are activated. Although they are characterized by a favorable risk/benefit ratio, immune checkpoint blockade has been associated with a new subset of autoimmune-like toxicities, named immune-related adverse events (irAE). Dermatologic reactions are among the most prevalent irAE triggered by CPIs. In a majority of cases they are self-limiting and readily manageable. However, it is not uncommon that they result in severe skin involvement and impairment of patients’ quality of life. Awareness of the spectrum of cutaneous irAEs is mandatory for every clinician involved in the management of oncologic patients. The role of the dermatologists is essential because early recognition and appropriate management of skin toxicity may prevent dose modifications and discontinuation of CPIs. The latter is particularly relevant, considering that recent data suggest favorable oncologic response in patients developing irAEs.  

A highly stable multifunctional aptamer for enhancing antitumor immunity against hepatocellular carcinoma by blocking dual immune checkpoints

2021 ◽  
Author(s):  
Yanlin Du ◽  
Da Zhang ◽  
Yiru Wang ◽  
Ming Wu ◽  
Cuilin Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints

A highly stable multifunctional aptamer was prepared for strengthening antitumor immunity through a dual immune checkpoint blockade of CTLA-4 and PD-L1.

scholarly journals Prospects of immune checkpoint blockade and vaccine-based immunotherapy for glioblastoma

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Stefanie Tietze ◽  
Susanne Michen ◽  
Gabriele Schackert ◽  
Achim Temme
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Primary Brain Tumor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Therapeutic Vaccines ◽  
Dismal Prognosis ◽  
Tumor Parenchyma ◽  
Immunosuppressive Microenvironment

Abstract Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor endowed with a dismal prognosis. Nowadays, immunotherapy in a particular immune checkpoint blockade and therapeutic vaccines are being extensively pursued. Yet, several characteristics of GBM may impact such immunotherapeutic approaches. This includes tumor heterogeneity, the relatively low mutational load of primary GBM, insufficient delivery of antibodies to tumor parenchyma and the unique immunosuppressive microenvironment of GBM. Moreover, standard treatment of GBM, comprising temozolomide chemotherapy, radiotherapy and in most instances the application of glucocorticoids for management of brain edema, results in a further increased immunosuppression. This review will provide a brief introduction to the principles of vaccine-based immunotherapy and give an overview of the current clinical studies, which employed immune checkpoint inhibitors, oncolytic viruses-based vaccination, cell-based and peptide-based vaccines. Recent experiences as well as the latest developments are reviewed. Overcoming obstacles, which limit the induction and long-term immune response against GBM when using vaccination approaches, are necessary for the implementation of effective immunotherapy of GBM.

scholarly journals Clinical management of immune-related adverse events following immunotherapy treatment in patients with non-small cell lung cancer

2021 ◽  
pp. jim-2021-001806
Author(s):  
Hannah Elizabeth Green ◽  
Jorge Nieva
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Mechanism Of Action ◽  
Immune Checkpoint ◽  
Clinical Management ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Checkpoint Blockade ◽  
Small Cell Lung ◽  
Autoimmune Conditions

The advent of checkpoint blockade-based immunotherapy is rapidly changing the management of lung cancer. Whereas past anticancer drugs’ primary toxicity was hematologic, the newer agents have primarily autoimmune toxicity. Thus, it is no longer enough for oncology practitioners to be skilled only in hematology. They must also understand management of autoimmune conditions, leveraging the skills of the rheumatologist, endocrinologist and gastroenterologist in the process. Herein we describe the mechanism of action and toxicities associated with immune checkpoint blockade in patients with lung cancer and provide a framework for management of adverse events.

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

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