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Nivolumab

Pembrolizumab

Atezolizumab

Immune Checkpoint Inhibitors

Avelumab

Durvalumab

Cemiplimab

Ipilimumab

Marie Hudson, MD

Manuel Flores, PhD

Marie Hudson, MD MPH

Immune checkpoint inhibitors (ICI) are among the most promising approaches to fighting cancer. However, a substantial percentage of patients experience off-target adverse effects in the form of mild to severe inflammation in different organs, commonly called immune-related adverse events (irAEs). irAEs can lead to treatment discontinuation, or can be life-threatening in extreme cases. The causes of irAEs are largely unknown and there are no reliable predictive biomarkers. The Montreal Immune-Related Adverse Events (MIRAE) study collects clinical information and biospecimens (blood, tissue, stool) from cancer patients treated with ICI to facilitate research on the identification of predictive biomarkers of irAEs, their causes, and the design of effective management strategies.

Background:

During cancer development and progression, cancer cells evolve to evade natural anti-tumor immunity. One major pathway of immune evasion involves the engagement of co-inhibitory receptors present on the surface of T cells that modulate their activation status, and therefore their ability to directly or indirectly kill tumor cells. These receptors are known as immune checkpoint inhibitors (ICI). Blockade of ICI using antibodies leads to prolonged T cell activation and unleashes the anti-tumor activity of T cells. ICI treatment for cancer has led to unprecedented advances in cancer treatment by prolonging survival of patients with previously refractory cancers. Among these ICI, CTLA-4, PD-1 and PDL-1 inhibitors have been shown to be effective cancer immunotherapies, and many other ICIs are now in pre-clinical and clinical development.

Although ICI cancer therapy is overall well tolerated, off-target immune reactions targeting healthy cells or tissues called immune-related adverse events (irAEs) develop in a substantial percentage of patients limiting the use of ICI therapy. irAEs target range from mild to severe and fatal. Currently, there are no reliable predictive biomarkers for the wide spectrum of irAEs and their clinical management in severe cases involves discontinuation of ICI therapy.

The Montreal Immune-Related Adverse Events (MIRAE) study is a biobank that collects human biological specimens (e.g., tissue, blood, plasma, PBMCs, saliva, stool) and the associated clinical information from cancer patients treated with ICI with the purpose of promoting research to identify clinical and biological predictors and mechanisms of irAEs, evaluate the effects of immunomodulatory treatment of irAEs on tumor biology, and investigate treatment strategies to minimize irAEs.

Objectives:

1. Identify biomarkers predictive of irAEs, including cellular, immunologic, genetic and microbial biomarkers; and
2. Evaluate the effects of immunomodulatory treatment of irAEs, and investigate treatment strategies that minimize irAEs and maximize ICI efficacy.

* Whole blood
* Peripheral blood mononuclear cells
* Stool
* Tissue biopsies

Montreal Immune-Related Adverse Events (MIRAE) Study

Montreal Database and Biorepository of Cancer Patients Treated With Immune Checkpoint Inhibitors for the Study of Immune-related Adverse Events

Sir Mortimer B. Davis - Jewish General Hospital

Marie Hudson, MD MPH FRCPC Principal Investigator, Rheumatologist, Division of Rheumatology and Department of Medicine, Jewish General Hospital and McGill University

Central Nervous System Depressants

Anti-Infective Agents

Respiratory System Agents

Anesthetics

Acetylcysteine

N-monoacetylcystine

Antiviral Agents

Expectorants

Antioxidants

Protective Agents

Antidotes

150mg/kg N-Acetylcysteine in 250mL Glucose 5% at time of induction of anaesthesia 50mg/kg N-Acetylcysteine in 250mL Glucose 5% on post-op days 1-3

placebo (250mL glucose 5%) at time of induction of anaesthesia placebo (250mL glucose 5%) on post-op days 1-3

n-acetylcysteine

250mL glucose 5%

Urs Zingg, PD, MD

Andreas Zollinger, MD

The purpose of this study is to evaluate the effect of high-dose n-acetylcysteine on inflammatory reaction, pulmonary morbidity, oxygenation and quality of life in patients undergoing transthoracic, partial or total resection of the esophagus for cancer.

Cancer of the esophagus has a poor long term prognosis as well as high perioperative morbidity. Pulmonary complications play thereby a major role. The standard procedure is either a combined transabdominal/transthoracic approach, which allows better visualisation of the tumor and more radical surgery (which may increase R0 resections and consequently overall survival) or a blunt transhiatal technique. In Zurich, Basel and Lucerne, the combined technique is the standard procedure. The combined surgical approach, pre-existing pulmonary disorders, poor nutritional status and the release of pro-inflammatory cytokines may be important contributing factors to pulmonary complications such as pneumonia, atelectasis, pleural effusions and the Acute Respiratory Distress Syndrome (ARDS). N-Acetylcysteine (NAC) has been shown to have direct and indirect oxygen scavenging abilities. In severe sepsis and acute respiratory distress syndrome, positive effects of NAC on morbidity and mortality were discovered. Aim of this study is to assess the influence of NAC on morbidity, oxygenation parameters and cytokine levels.

According to power analysis, 90 patients have to be included in the trial. A multicenter approach was chosen to finish the study within 3 years. Respective to the average number of operations per institution and year, the following distribution is planned: Triemli Hospital 40, University Hospital Basel 30, Kantonsspital Lucerne 20. Inclusion criteria for this trial are patients undergoing thoraco-abdomino-cervical or abdomino-thoracic esophagectomy for cancer between 20 and 90 years and given informed consent. Exclusion criteria are known allergy or hypersensitivity to NAC and pregnancy. Patients are randomised to receive either high dose N-Acetylcysteine administered perioperatively and postoperatively for three days (150mg/kg perioperatively and 50mg/kg days 1-3) or placebo (glucose 5%).

Pre-, peri- and postoperatively cytokines (IL-1, IL-1ra, IL-6, IL-8, IL-10, TNF-α), are quantified by enzyme-linked immuno assay (ELISA) from blood, broncho-alveolar lavage and lavage of pleural space. Leucocytes, C-reactive protein, Procalcitonin and oxygenation parameters (arterial blood gas analyses = ABGA) are regularly measured. Morbidity and mortality is assessed. Furthermore, all patients are asked to complete a quality of life questionnaire (EORTC QLQ-OES18 and 30, SF-36) before and after the operation (12, 24, 36 months post-op).

Influence of N-Acetylcysteine on Morbidity, Oxygenation and Cytokine Levels in Partial or Total Esophagectomy for Cancer

Influence of N-Acetylcysteine on Morbidity, Oxygenation and Cytokine Levels in Partial or Total Esophagectomy for Cancer. A Multicenter, Prospective, Randomised Double Blind, Placebo-controlled Study

Triemli Hospital

University Hospital, Basel, Switzerland

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

Behaviors and Mental Disorders

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Quality of Life

patients received pulmonary lobectomy under general anesthesia by using uni-portal VATS method

uni-portal VATS group

patients received pulmonary lobectomy under under general anesthesia by using three port VATS method

three port VATS group

Many recent studies have shown that surgical trauma will result in an immunosuppressive state. Combined with the effect of surgical stress, it will often lead to metabolic changes, systemic inflammatory response, and other problems. The body resists and removes the harmful factors through the inflammatory reaction. However, an excessive reaction will damage the normal tissues and cells of the body. The smooth recovery of the body needs to balance the degree of inflammatory reaction. Surgical patients will trigger different degrees of an inflammatory response due to different degrees of physical trauma, which runs through the process of postoperative recovery from the beginning of surgery and often prolongs the time of postoperative recovery. Reducing the intraoperative and postoperative inflammatory response of patients has always been the goal of surgeons, and a method is the reduction of surgical trauma.

The successful experience of the first single-port thoracoscopic wedge resection of the lung in 2004 provided us with a new surgical idea. Subsequently, a large number of domestic and international studies and case reports show that single-port thoracoscopic surgery is safe and feasible in lobectomy and segmental resection. With the rapid development of single-port thoracoscopic surgery in recent years, the scope of application and clinical efficacy of the surgery are gradually becoming equivalent to the traditional three-port thoracoscopic surgery, which can ensure the safety of the operation and complete tumor resection, and has its own characteristics and advantages compared with the traditional three-port thoracoscopic surgery. The reduction of incisions can significantly improve the postoperative pain and recovery of patients and wound healing.

In addition, single-port thoracoscopic surgery also has a subtle improvement in patients' intraoperative and postoperative inflammatory response compared with traditional three-port thoracoscopic surgery. In this study, we compared and analyzed the intraoperative and postoperative inflammatory factor levels of single-port thoracoscopic surgery and three-port thoracoscopic surgery in patients with non-small cell lung cancer (NSCLC). Through the comparison of the measured values, we further discussed the advantages of single-port thoracoscopic surgery in reducing inflammatory response and its application and promotion value in the treatment of patients with NSCLC compared with traditional three-port thoracoscopic surgery.

Comparison of Inflammatory Cytokine Levels Between Single-port and Three-port Thoracoscopic Lobectomy in the Treatment of Non-small Cell Lung Cancersurgery on Perioperative Clinical Indexes、Inflammatory Reaction and Quality of Life Scores of Patients With Non-small Cell Lung Cancer

Comparison of Inflammatory Cytokine Levels Between Single-port and Three-port Thoracoscopic Lobectomy in the Treatment of Non-small Cell Lung Cancer

record intraoperative hemorrhage volume at the end of the surgery

record chest drainage time until remove drainage tube

record the duration of the healing of incision

record the days of patients' out-of-bed activity time and length of hospital stay after surgery

record postoperative pain 24 hours after surgery by using visual analog scale (VAS) score, where 0 indicates painlessness, and 10 indicates severe pain

record postoperative adverse effects 24 hours after surgery

record serum amyloid A protein (SAA) after surgery

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Montreal Immune-Related Adverse Events (MIRAE) Study	NCT05139706	Cancer Immune System D... Inflammatory Re... Autoimmune Dise...		18 Years - 100 Years	Sir Mortimer B. Davis - Jewish General Hospital
Influence of N-Acetylcysteine on Morbidity, Oxygenation and Cytokine Levels in Partial or Total Esophagectomy for Cancer	NCT00512265	Pulmonary Morbi...	n-acetylcystein... 250mL glucose 5...	20 Years - 90 Years	University Hospital, Basel, Switzerland
Montreal Immune-Related Adverse Events (MIRAE) Study	NCT05139706	Cancer Immune System D... Inflammatory Re... Autoimmune Dise...		18 Years - 100 Years	Sir Mortimer B. Davis - Jewish General Hospital
Comparison of Inflammatory Cytokine Levels Between Single-port and Three-port Thoracoscopic Lobectomy in the Treatment of Non-small Cell Lung Cancersurgery on Perioperative Clinical Indexes、Inflammatory Reaction and Quality of Life Scores of Patients With Non-small Cell Lung Cancer	NCT05070026	Video-assisted ... Inflammatory Re... Life Scores	uni-portal VATS... three port VATS...	18 Years - 75 Years	Shengjing Hospital

Spots Global Cancer Trial Database for inflammatory reaction