Immune checkpoint inhibitors: For how long do we need to release the brakes to achieve the optimum acceleration of immune-mediated anti-tumor response?

Multiple drugs of a new class of cancer treatments called immune checkpoint inhibitors, which work by enabling the immune system to attack tumour cells, have been approved for a variety of indications in recent years. Immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 and programmed death-1, are part of the normal immune system and regulate immune activation. Treatment with inhibitors of these checkpoints can significantly improve response rates, progression-free survival and overall survival of patients with cancer; it can also result in adverse reactions that present similarly to other conditions. These immune-mediated adverse reactions (IMARs) are most commonly gastrointestinal, respiratory, endocrine or dermatologic. Although patients’ presentations may appear similar to other types of cancer therapy, the underlying causes, and consequently their management, may differ. Prompt recognition is critical because, with appropriate management, most IMARs resolve and patients can continue receiving immune checkpoint inhibitor treatment. Rarely, these IMARs may be life-threatening and escape detection from the usual evaluations in the emergency environment. Given the unusual spectrum and mechanism of IMARs arising from immune checkpoint inhibitors, emergency departmentED staff require a clear understanding of the evaluation of IMARs to enable them to appropriately assess and treat these patients. Treatment of IMARs, most often with high-dose steroids, differs from chemotherapy-related adverse events and when possible should be coordinated with the treating oncologist. This review summarises the ED presentation and management of IMARs arising from immune checkpoint inhibitors and includes recommendations for tools and resources for ED healthcare professionals.

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Workup and Management of Immune‐Mediated Colitis in Patients Treated with Immune Checkpoint Inhibitors

The Oncologist ◽

10.1634/theoncologist.2018-0304 ◽

2019 ◽

Vol 25 (3) ◽

pp. 197-202 ◽

Cited By ~ 1

Author(s):

Bhavana Pendurthi Singh ◽

John L. Marshall ◽

Aiwu Ruth He

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Immune Mediated

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Association of antibiotic exposure with overall survival and colitis in patients with stage III and IV melanoma receiving immune checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.56 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 56-56

Author(s):

Brian Chu ◽

Jahan J. Mohiuddin ◽

Andrea Facciabene ◽

Xingmei Wang ◽

Abigail Doucette ◽

...

Keyword(s):

Overall Survival ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Stage Iii ◽

Secondary Outcome ◽

Future Research ◽

Antibiotic Exposure ◽

Primary Analysis ◽

Immune Mediated

56 Background: Recent studies suggest that changes in the gut microbiome modulate response to cancer treatment, including immune checkpoint inhibitors (ICI). Broad-spectrum antibiotics (Abx) are known to cause significant dysbiosis. We hypothesize that recent Abx exposure worsens outcomes in patients (pts) with stage III/IV melanoma (MM) receiving ICI. Methods: We identified MM pts treated with ICI from our institutional database. All received their first ICI between 2004-2019. Antibiotic exposure was defined as receipt of Abx within 3 months prior to the first infusion of ICI. The primary outcome was overall survival (OS) and the secondary outcome was immune-mediated colitis requiring intravenous (IV) steroids. Stage III and IV pts were analyzed separately for the primary analysis. Results: Of 568 pts in our database, 20% received Abx within the 3 months prior to ICI. 36% of pts had stage III disease and 26% of pts were treated with either adjuvant or neoadjuvant ICI. 1.6% of pts died of causes other than MM. The Abx+ and Abx- groups were balanced in terms of stage, race, age, sex, BRAF status, LDH, prior systemic therapies, and class of ICI received. Only 4 pts were hospitalized due to the infection prompting the Abx, and no pts died due to the infection. In the Stage IV group, Abx+ pts had worse OS on MV analysis (HR 1.6, 95% CI 1.1-2.2). Stage III Abx+ also had worse OS (HR 2.8, 95% CI 1.3-5.9). In a sensitivity analysis excluding pts who received IV Abx or were admitted due to infection, survival was still worse for Abx+ pts (HR 1.7, 95% CI 1.2-2.4). In a Fine-Grey competing risk MV model, Abx+ had a higher rate of immune-mediated colitis requiring IV steroids (HR 2.1, 95% CI 1.02-4.5). Conclusions: In MM pts treated with ICI, receipt of Abx within 3 months prior to ICI initiation was associated with decreased OS and increased colitis. Future research should include prospective studies to better define the risk/benefit profile of antibiotics in close proximity to ICI. [Table: see text]

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Immuno-related endocrinopathy in patients treated with immune checkpoint inhibitors

Medical Council ◽

10.21518/2079-701x-2020-9-16-24 ◽

2020 ◽

pp. 16-24

Author(s):

D. I. Yudin ◽

K. K. Laktionov ◽

K. A. Sarantseva ◽

O. I. Borisova ◽

V. V. Breder ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Clinical Practice ◽

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Serious Adverse Events ◽

Immune Mediated ◽

Discontinuation Of Treatment ◽

The Russian Federation

Recently immune checkpoint inhibitors amazingly changed the landscape of cancer therapy worldwide. The number of immune checkpoint molecules in clinical practice is constantly increasing. There are some monoclonal antibodies recently registered in the Russian Federation: anti-PD1 antibodies (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab), anti-CTLA-4 (ipilimumab). Immune-mediated endocrinopathies are some of the most common complications of immunotherapy. According to the results of clinical studies, the incidence of serious endocrine immuno-mediated adverse events with anti-PD1 monoclonal antibodies is low (3.5–8%). The use of anti-CTLA4 antibodies, combined regimens, and the use of immunotherapy after chemoradiotherapy significantly increase the incidence of serious adverse events to 30%. In clinical practice of N.N. Blokhin Cancer Research Center among 245 non-small cell lung cancer and hepatocellular carcinoma patients treated with immunotherapy, 22 (8,9%) developed an immune-mediated endocrinopathy. Most patients developed adverse events of 1–2 degrees, in two patients – 3 degrees, requiring discontinuation of treatment. The aim of this article was to provide useful information and recommendations regarding the management of common immuno-related endocrine adverse events (including hypothyroidism, hyperthyroidism, pituitary, adrenal insufficiency) for clinical oncologists.

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Hepatic Immune-Mediated-Adverse-Effects of Immune Checkpoint Inhibitors: Analysis of Real-Life Experience

Annals of Hepatology ◽

10.1016/j.aohep.2021.100561 ◽

2021 ◽

pp. 100561

Author(s):

Joana Alves da Silva ◽

Daniela Falcão ◽

Cláudia Cardoso ◽

Ana Luísa Pires ◽

António Araújo ◽

...

Keyword(s):

Adverse Effects ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Life Experience ◽

Checkpoint Inhibitors ◽

Real Life ◽

Immune Mediated

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Immune-mediated adverse events in immune checkpoint inhibitors therapy: literature review

Modern Oncology ◽

10.26442/18151434.2021.2.200502 ◽

2021 ◽

Vol 23 (2) ◽

pp. 319-326

Author(s):

Marina A. Lyadova ◽

Vladimir K. Lyadov

Keyword(s):

Adverse Events ◽

Interstitial Nephritis ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Acute Interstitial Nephritis ◽

Early Symptom ◽

Immune Mediated ◽

Cutaneous Rash ◽

Pancreatic Dysfunction

Immune-mediated adverse events (imAEs) are complications of therapy with immune checkpoint inhibitors, which arise as a result of autoimmune inflammation. The article summarizes systemic (fatigue, fever), cutaneous (rash, itching), gastrointestinal (diarrhea, colitis, hepatitis, pancreatic dysfunction), endocrinological (hypothyroidism, hypophysitis, adrenal insufficiency, diabetes mellitus), pulmonary (pneumonitis, pleuritis), rheumatological (arthralgia), neurological (headache, sensory and motor disorders), renal (acute interstitial nephritis, lupus-like nephritis, granulomatous nephritis, diffuse interstitial nephritis and minimal change disease), hematological (anemia, cytopenia), cardiovascular (myocarditis) and ocular (conjunctivitis, episcleritis, ceratitis, blepharitis and uveitis) imAE. Pathogenetic mechanisms and treatment approaches (in accordance with toxicity grade and clinical recommendations) are discussed. Early symptom recognition, patient education and timely intervention are crucial for imAE correction.

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Immune-Mediated Colitis

Current Treatment Options in Gastroenterology ◽

10.1007/s11938-019-00263-0 ◽

2019 ◽

Vol 17 (4) ◽

pp. 506-523

Author(s):

Tara Menon ◽

Anita Afzali

Keyword(s):

Inflammatory Bowel Disease ◽

Monoclonal Antibodies ◽

Immune System ◽

Immune Checkpoint Inhibitors ◽

Tumor Response ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Immune Mediated ◽

Wide Range ◽

Inflammatory Bowel

Abstract Purpose of review This review addresses our current knowledge of immune-mediated colitis (IMC) and offers a practical guide to its management. Recent findings Due to the similarity in clinical, endoscopic, and histologic findings between IMC and inflammatory bowel disease (IBD), gastroenterologists have tailored their approach to IMC management to that of IBD. Summary Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that augment the T-cell anti-tumor response of the immune system and have demonstrated their importance in the treatment of a wide range of malignancies. With the growing benefits of ICIs, there are immune-related adverse events (irAEs) that mirror many known autoimmune diseases. Diarrhea and IMC are the most common and severe irAEs noted. No standardized guidelines exist in the management of these irAEs.

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