Immune Checkpoint Inhibitor Cardiotoxicity: Understanding Basic Mechanisms and Clinical Characteristics and Finding a Cure

Immune checkpoint inhibitors (ICIs) attenuate mechanisms of self-tolerance in the immune system, enabling T cell responses to cancerous tissues and revolutionizing care for cancer patients. However, by loweringbarriers against self-reactivity, ICIs often result in varying degrees of autoimmunity. Cardiovascular complications, particularly myocarditis but also arrhythmias, pericarditis, and vasculitis, have emerged as significant complications associated with ICIs. In this review, we examine the clinical aspects and basic science principles that underlie ICI-associated myocarditis and other cardiovascular toxicities. In addition, we discuss current therapeutic approaches. We believe a better mechanistic understanding of ICI-associated toxicities can lead to improved patient outcomes by reducing treatment-related morbidity.

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Evaluation and clinical impact of a pharmacist-led, interdisciplinary service focusing on education, monitoring and toxicity management of immune checkpoint inhibitors

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211061133 ◽

2021 ◽

pp. 107815522110611

Author(s):

Glenn Myers ◽

Jonathan Stevens ◽

Andrew Flewelling ◽

Jacqueline Richard ◽

Meagan London

Keyword(s):

Adverse Event ◽

Patient Outcomes ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Study Cohort ◽

Control Cohort ◽

Related Adverse Event

Introduction Immune-related adverse events are complications of immune checkpoint inhibitors which require robust patient education and proactive follow-up to ensure timely identification and management. Oncology pharmacist practice models with other anticancer modalities have been well documented, but there is limited evidence assessing the spectrum of pharmacist interventions in patients receiving immune checkpoint inhibitor(s) and the impact of these interventions on patient outcomes. Methods Patients initiated on immune checkpoint inhibitor(s) from 1 January 2016 to 31 August 2019 were included for data collection and analysis. Part 1 featured an intensive pharmacist follow-up cohort (study cohort) and summarized pharmacist interventions. Part 2 compared patient outcomes between the study cohort and a standard of care cohort (control cohort) from a different oncology centre. Patient outcomes included emergency department visits not resulting in admission, hospitalizations due to immune-related adverse event(s), immune checkpoint inhibitor cycles received, treatment discontinuation due to immune-related adverse event(s), completion of finite programmed death-1/death-1 ligand treatment course and completion of ipilimumab. Clinical outcomes were compared using a retrospective, matched cohort design based on age, cancer diagnosis and immune checkpoint inhibitor(s). Results A total of 143 patients were included in Part 1 encompassing 1664 pharmacist recommendations across 11 categories. The matched cohort yielded 92 matches (n = 184) with a higher odds of immune checkpoint inhibitor discontinuation due to immune-related adverse event(s) in the control cohort (odds ratio (OR) (95% confidence interval (CI)) = 5.5 (1.2−24.8); p = 0.022). Conclusion Intensive immune-related adverse event education, proactive follow-up and immune-related adverse event management by pharmacists result in clinically meaningful interventions which correlate to improved patient outcomes, namely lower odds of treatment discontinuation due to immune-related adverse event(s).

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CMV coinfection in treatment refractory immune checkpoint inhibitor colitis

BMJ Case Reports ◽

10.1136/bcr-2019-233519 ◽

2020 ◽

Vol 13 (5) ◽

pp. e233519

Author(s):

Kevin B Harris ◽

Pauline Funchain ◽

Brian B Baggott

Keyword(s):

Case Report ◽

Patient Outcomes ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Treatment Refractory ◽

Cmv Colitis ◽

Improve Patient

As immune checkpoint inhibitors (ICIs) are increasingly used, clinicians are more frequently encountering the side effects of these therapies. ICIs have been implicated in numerous adverse effects against healthy tissues. We present a case of a patient who developed treatment refractory checkpoint inhibitor colitis. Following colonoscopy, it was discovered that this patient had cytomegalovirus (CMV) coinfection. This case report highlights the importance of undertaking an appropriate assessment, including endoscopic and histologic investigation, of patients with presumed ICI colitis. Accurately diagnosing a superimposed CMV colitis changes clinical management and can improve patient outcomes.

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Immune Checkpoints in Cancers: From Signaling to the Clinic

Cancers ◽

10.3390/cancers13184573 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4573

Author(s):

Céline Pisibon ◽

Amira Ouertani ◽

Corine Bertolotto ◽

Robert Ballotti ◽

Yann Cheli

Keyword(s):

Immune System ◽

Patient Outcomes ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Mechanisms Of Action ◽

Immune Checkpoints

The immune system is known to help fight cancers. Ten years ago, the first immune checkpoint inhibitor targeting CTLA4 was approved by the FDA to treat patients with metastatic melanoma. Since then, immune checkpoint therapies have revolutionized the field of oncology and the treatment of cancer patients. Numerous immune checkpoint inhibitors have been developed and tested, alone or in combination with other treatments, in melanoma and other cancers, with overall clear benefits to patient outcomes. However, many patients fail to respond or develop resistance to these treatments. It is therefore essential to decipher the mechanisms of action of immune checkpoints and to understand how immune cells are affected by signaling to be able to understand and overcome resistance. In this review, we discuss the signaling and effects of each immune checkpoint on different immune cells and their biological and clinical relevance. Restoring the functionality of T cells and their coordination with other immune cells is necessary to overcome resistance and help design new clinical immunotherapy strategies. In this respect, NK cells have recently been implicated in the resistance to anti-PD1 evoked by a protein secreted by melanoma, ITGBL1. The complexity of this network will have to be considered to improve the efficiency of future immunotherapies and may lead to the discovery of new immune checkpoints.

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The emerging use of immune checkpoint blockade in the adjuvant setting for solid tumors: a review

Immunotherapy ◽

10.2217/imt-2019-0087 ◽

2019 ◽

Vol 11 (16) ◽

pp. 1409-1422 ◽

Cited By ~ 9

Author(s):

Elissar Moujaess ◽

Fady Gh Haddad ◽

Roland Eid ◽

Hampig Raphael Kourie

Keyword(s):

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Adjuvant Setting ◽

Lung Cancers ◽

Metastatic Setting ◽

Postoperative Setting

The use of immune checkpoint inhibitors has been approved in the advanced and metastatic setting for many types of solid tumors. Nonetheless, their role in the adjuvant setting is limited to the treatment of surgically resected melanoma. Ipilimumab was the first immune checkpoint inhibitor approved for this indication, followed by nivolumab and pembrolizumab. Many ongoing trials are evaluating these molecules in the postoperative setting, alone or in combination with other therapies. Preliminary results are promising regarding the treatment of other cutaneous tumors, lung cancers, head and neck squamous cell carcinomas, bladder cancer and renal cell carcinomas. Some data assessing their use for the adjuvant treatment of esophageal, colorectal, ovarian cancer and other solid tumors are similarly emerging.

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Enterococcus peptidoglycan remodeling promotes immune checkpoint inhibitor therapy

10.1101/2020.08.20.256263 ◽

2020 ◽

Author(s):

Matthew E. Griffin ◽

Juliel Espinosa ◽

Jessica L. Becker ◽

Jyoti K. Jha ◽

Gary R. Fanger ◽

...

Keyword(s):

Antitumor Activity ◽

Immune Checkpoint ◽

Molecular Mechanisms ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Mouse Tumor ◽

Peptidoglycan Hydrolases ◽

Checkpoint Inhibitor Therapy ◽

Specific Species

AbstractThe antitumor efficacy of cancer immunotherapy has been correlated with specific species within the gut microbiota. However, molecular mechanisms by which these microbes affect host response to immunotherapy remain elusive. Here we show that specific members of the bacterial genus Enterococcus can promote anti-PD-L1 immunotherapy in mouse tumor models. The active enterococci express and secrete orthologs of the NlpC/p60 peptidoglycan hydrolase SagA that generate immune-active muropeptides. Expression of SagA in non-protective E. faecalis was sufficient to promote antitumor activity of clinically approved checkpoint targets, and its activity required the peptidoglycan sensor Nod2. Notably, SagA-engineered probiotics or synthetic muropeptides also promoted checkpoint inhibitor antitumor activity. Our data suggest that microbiota species with unique peptidoglycan remodeling activity may enhance immunotherapy and could be leveraged for next-generation adjuvants.One Sentence SummaryA conserved family of secreted NlpC/p60 peptidoglycan hydrolases from Enterococcus promote antitumor activity of immune checkpoint inhibitors.

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Application of Immune Checkpoint Inhibitors in the Treatment of Cholangiocarcinoma

Technology in Cancer Research & Treatment ◽

10.1177/15330338211039952 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110399

Author(s):

Fan-li Zeng ◽

Jing-fang Chen

Keyword(s):

Solid Tumors ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Malignant Tumors ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

General Term ◽

Distal Cholangiocarcinoma ◽

Poor Outcomes ◽

Defective Mismatch Repair

Cholangiocarcinoma is a general term for intrahepatic and extrahepatic malignant tumors deriving in the biliary system. According to the location, it is divided into intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma. Progressive cholangiocarcinoma yields poor outcomes with radiotherapy; therefore, there is an urgent need for new therapeutic breakthroughs. Immune checkpoint inhibitor (ICI) therapy brings the treatment for cancer into a new field, with the use of drugs targeting PD-1/PD-L1 and CTLA-4 considerably extending the survival of patients with melanoma, lung cancer, and other solid tumors. The FDA has approved the application of pembrolizumab for solid tumors with high microsatellite instability and defective mismatch repair, including cholangiocarcinoma. Moreover, the combination of ICIs with chemotherapy and radiation therapy showed good promise. The aim of the present study was to review the application of ICIs in the treatment of cholangiocarcinoma and to summarize the reported individualized immunotherapy-based protocols and ongoing clinical trials for clinical reference.

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Efficacy of immunotherapy in hepatocholangiocarcinoma (HCC-CC): Proof of concept.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16194 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16194-e16194

Author(s):

Osama Diab ◽

Maloree Khan ◽

Saqib Abbasi ◽

Anwaar Saeed ◽

Anup Kasi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Line Treatment ◽

First Line ◽

Liver Cancers ◽

First Line Treatment

e16194 Background: Hepatocholangiocarcinoma (HCC-CC) is a rare form of cancer with a poor prognosis. Of all primary liver cancers, the incidence of HCC-CC ranges from 0.4 to 14.2%. HCC-CC is a mixed carcinoma with findings of both hepatocellular carcinoma and cholangiocarcinoma. Immune checkpoint inhibitors are a potent first line treatment in hepatocellular carcinoma with multiple clinical trial showing effectiveness in cholangiocarcinoma. HCC-CC has limited proven treatment options as patients are generally excluded from clinical trials. In this study we reviewed outcomes of patients with HCC-CC who received immune checkpoint inhibitor in a single center. Methods: Records of patients who had a pathological confirmed HCC-CC by a subspecialized hepatic pathologist at the University of Kansas medical center were reviewed. We identified 6 patients with locally advanced unresectable or metastatic HCC-CC that received immune checkpoint inhibitor between February 2017 and January 2021. Baseline characteristics were obtained, as well as best response, line of therapy, and duration of response. Results: Of the six patients 4 (66%) received PD-1 inhibitor alone and 2 (34%) received combination therapy with CTLA-4 inhibitor for the treatment of HCC-CC. There were 3 (50%) females and 6 (100%) with prior hepatitis C infection. four (66%) patients had metastatic disease and 2 had locally unresectable advanced disease. Objective response rate was 83.3%. One patient achieved complete response and had a treatment holiday after receiving treatment for 2 years, and restarted immunotherapy upon relapse. Four patients had a partial response, of which two passed away after disease progression. One patient had stable disease on 2 different lines of immunotherapy then progressed. Of those who responded, one patient received immunotherapy, 3 (50%) received liver directed therapy and two received chemotherapy or Lenvatinib as first line treatment (Table). Conclusions: Immune checkpoint inhibitors demonstrate potential activity in patients with HCC-CC without unexpected side effect in this unmet need high-risk population. Larger studies are needed to confirm activity and efficacy in this setting.[Table: see text]

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Immune checkpoint inhibitor sensitivity of DNA repair deficient tumors

Immunotherapy ◽

10.2217/imt-2021-0024 ◽

2021 ◽

Vol 13 (14) ◽

pp. 1205-1213

Author(s):

Pauline Rochefort ◽

Françoise Desseigne ◽

Valérie Bonadona ◽

Sophie Dussart ◽

Clélia Coutzac ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Immune Checkpoint ◽

Genome Stability ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Excision Repair ◽

Checkpoint Inhibitors ◽

Repair Deficiency ◽

Dna Repair Deficiency

Faithful DNA replication is necessary to maintain genome stability and implicates a complex network with several pathways depending on DNA damage type: homologous repair, nonhomologous end joining, base excision repair, nucleotide excision repair and mismatch repair. Alteration in components of DNA repair machinery led to DNA damage accumulation and potentially carcinogenesis. Preclinical data suggest sensitivity to immune checkpoint inhibitors in tumors with DNA repair deficiency. Here, we review clinical studies that explored the use of immune checkpoint inhibitor in patient harboring tumor with DNA repair deficiency.

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Venous thromboembolism events in patients with advanced cancer on immune checkpoint inhibitors

Immunotherapy ◽

10.2217/imt-2021-0151 ◽

2021 ◽

Author(s):

Adi Kartolo ◽

Cynthia Yeung ◽

Gordon T Moffat ◽

Lilian Hanna ◽

Wilma Hopman ◽

...

Keyword(s):

Venous Thromboembolism ◽

Advanced Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Cancer Management ◽

Thromboembolism Events

Aim: To evaluate the correlation between venous thromboembolism events (VTEs) and immune checkpoint inhibitor (ICI)-based regimens. Methods: This is a retrospective study of 403 patients with advanced cancer on ICI-based regimens. Results: We report 8% VTE incidence post-ICI initiation over a median of 11.1 months of follow-up. Compared with single-agent ICI, dual-ICI was significantly correlated with higher incidence of VTE (odds ratio [OR]: 4.196, 95% CI: 1.527–11.529, p = 0.005), but chemotherapy–immuno-oncology combination was not (OR: 1.374, 95% CI: 0.285–6.632, p = 0.693). Subsequent systemic therapy post-ICI was also independently associated with higher VTE incidence (OR: 2.599, 95% CI: 1.169–5.777, p = 0.019). Conclusion: Our findings suggest potential underreporting of VTE incidence in ICI clinical trials. As dual-ICI is becoming more prevalent in cancer management, clinicians should maintain vigilance regarding VTE in patients with advanced cancer on ICI-based regimens.

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Peritoneal melanosis associated with metastatic melanoma previously treated with targeted and immune checkpoint inhibitor therapy

BMJ Case Reports ◽

10.1136/bcr-2020-238235 ◽

2021 ◽

Vol 14 (1) ◽

pp. e238235

Author(s):

Kwang Kiat Sim ◽

Katie Connell ◽

Mayank Bhandari ◽

David Paton

Keyword(s):

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Inhibitor Therapy ◽

Tumour Regression ◽

Benign Condition ◽

Checkpoint Inhibitor Therapy ◽

Previously Treated

Peritoneal melanosis is an uncommon benign condition, the pathophysiology of which is unclear. Macroscopically, it appears as diffuse dark brown or black pigmentation within the peritoneum, mimicking more sinister conditions such as metastatic melanoma. It has been described in a variety of contexts, but only exceedingly rarely in association with metastatic melanoma, with only two previous published case reports. We present a case of peritoneal melanosis associated with metastatic melanoma involving the spleen, previously treated with targeted and immune checkpoint inhibitor therapy. With increasing reports of melanoma regression manifesting as cutaneous tumorous melanosis in patients treated with immune checkpoint inhibitors, we postulate that, similarly, immunotherapy and tumour regression might have a role to play in the pathogenesis of the peritoneal pigmentation in this case.

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