Immune Checkpoint Inhibitor–Mediated Diarrhea and Colitis: A Clinical Review

2020 ◽  
Vol 16 (8) ◽  
pp. 453-461 ◽  
Author(s):  
Zimu Gong ◽  
Yinghong Wang
Keyword(s):  
Immune Checkpoint ◽  
Fecal Microbiota Transplantation ◽  
Checkpoint Inhibitors ◽  
Management Strategies ◽  
Surrogate Marker ◽  
Patient Characteristics ◽  
Fecal Microbiota ◽  
Screening Tools ◽  
Fecal Lactoferrin ◽  
Cancer Outcome

Immune-mediated diarrhea and colitis (IMDC) is among the most common immune-related adverse events in patients with cancer treated with immune checkpoint inhibitors (ICIs). Many factors will affect the risk of IMDC, including the type of ICI used, the type of underlying cancer, and patient characteristics. A recent study showed that preexisting inflammatory bowel disease significantly increases the risk of diarrhea and colitis with ICI treatment. In terms of management, early endoscopic evaluation improves clinical outcome by identifying high-risk patients who will benefit from early add-on immunosuppressants. Inflammatory markers, including fecal lactoferrin and calprotectin, are good screening tools to predict which patients are at risk for colitis. Calprotectin especially is associated with colitis outcome and can be used as a surrogate marker to follow treatment response. Corticosteroids remain the first-line medical treatment of IMDC management, and add-on therapy with vedolizumab or infliximab should be considered in selected patients. Fecal microbiota transplantation may be considered in refractory cases. The decision to resume ICI should be decided by balancing the risk of recurrent IMDC and the likelihood of benefiting from further ICI treatment. There is no clear evidence about whether the use of immunosuppressants will result in a worse cancer outcome. With emerging evidence, our understanding and management strategies are likely to evolve in the future.

Is chronic refractory colitis from immune checkpoint inhibitor associated with good cancer outcome?

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15102-e15102
Author(s):  
Weijie Ma ◽  
Anusha Thomas ◽  
Yinghong Wang
Keyword(s):  
Immune Checkpoint ◽  
Clinical Remission ◽  
Checkpoint Inhibitors ◽  
Surrogate Marker ◽  
Lymphocytic Colitis ◽  
Chronic Inflammatory Condition ◽  
Long Term Treatment ◽  
Cancer Outcome ◽  
Histological Remission

e15102 Background: Immune checkpoint inhibitors (ICIs) are efficacious in treating many advanced malignancies. However, drug induced colitis limits their use significantly. We present cases with chronic refractory ICI colitis requiring long term immunosuppressive therapy and favorable cancer outcomes. Methods: We identified 3 cases who developed ICI colitis and persisted for longer than 6 months requiring long term immunosuppressant therapy. The patients’ clinical data was collected. Results: All patients were male, with median age of 55. Two had melanoma, one urothelial cancer. All patients received PD-1(L)-1 agents with colitis onset about 3-6 months after ICI treatment. All patients were taken off ICI permanently due to colitis over a duration of 19-30 months (peak grade of 3). Endoscopy of all three were grossly unremarkable, with lymphocytic colitis on pathology in all three. Patient A’s colitis achieved clinical and histological remission after 5 doses of vedolizumab, however recurred after 9 months with biopsy proven recurrence. Current management is anti-diarrheal medication given mild symptom. Patient B had more aggressive disease, with first recurrence after 2 doses of infliximab and steroid, achieved initial histological remission after 3 doses of vedolizumab and 2 additional infliximab, then had 2nd recurrence after 3 months. Fecal microbiota transplantation as compassionate treatment was not effective. Thereafter, patient was resumed on vedolizumab ever since with clinical remission. Last histology evaluation showed persistent lymphocytic colitis 30 months after initial diagnosis. The third case had initial histological remission after 3 doses of vedolizumab, followed by recurrence after 4 months, which triggered another 3 doses of vedolizumab, with persistent grade 3 diarrhea despite resolution of histological inflammation after total 6 doses of vedolizumab. Patient was subsequently treated with steroid and ustekinumab with clinical remission. At the end of follow up, all three patients have sustained cancer remission over 19-31 months. Conclusions: IMC is a common adverse event from ICI, and could progress to a chronic inflammatory condition that require long term treatment. Histological remission does not preclude future recurrence of colitis. Persistent toxicity could be a surrogate marker for enduring ICI effect which may be associated with favorable cancer outcome. Long term immunosuppression can be essential for refractory ICI colitis cases for clinical remission.

scholarly journals Impact of the gut microbiome on immune checkpoint inhibitor efficacy— a systematic review

2019 ◽  
Vol 26 (6) ◽  
Author(s):  
J. Pierrard ◽  
E. Seront
Keyword(s):  
Systematic Review ◽  
Gut Microbiome ◽  
Immune Checkpoint ◽  
Full Text ◽  
Fecal Microbiota Transplantation ◽  
Checkpoint Inhibitors ◽  
Fecal Microbiota ◽  
Associated Bacteria ◽  
Anticancer Efficacy ◽  
Negative Effect

Background Immune checkpoint inhibitors (icis) are increasingly being used in clinical practice, improving outcomes for cancer patients. Preclinical models showed significant interaction between the gut microbiome (gm) and response to icis. However, that interaction remains unclear in clinical practice.Methods We performed a systematic review in medline to determine■ whether antibiotics affect ici efficacy,■ whether baseline gm composition and ici efficacy show any correlations,■ whether baseline gm composition and emergence of immune-related adverse events (iraes) show any correlations, and■ whether gm manipulation can alleviate the iraes.Included publications had to be written in English or French and had to describe a quantifiable link between gm composition or its modification and the response to icis or the occurrence of iraes, or both.Results Of 1451 articles published before December 2018, 13 publications met the inclusion criteria. Five full-text articles and two abstracts highlighted a negative effect of antibiotics on ici efficacy. The composition of the gm was associated with ici efficacy in five full-text articles and one abstract, and with iraes in two full-text articles. In 2 cases, fecal microbiota transplantation was reported to reduce immune colitis.Conclusions If possible, antibiotics should be avoided before ici treatment because of their negative effect on ici anticancer efficacy. No specific commensal bacterium was associated with ici efficacy, but an intact gm with high bacterial diversity and a good ratio of “responder-associated” bacteria to “non-responder-associated” bacteria seem to be correlated with better patient outcomes. Fecal microbiota transplantation is a promising technique for reducing ici-associated colitis.

scholarly journals 2579. Impact on the Gut Microbiota of the Prolonged Antimicrobial Therapy in Patients with Bone and Joint Infection (BJI): Results From the OSIRIS Prospective Study in France

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S896-S896
Author(s):  
Benoit Levast ◽  
Cécile Batailler ◽  
Cécile Pouderoux ◽  
Lilia Boucihna ◽  
Sébastien Lustig ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Joint Infection ◽  
Surrogate Marker ◽  
Generation Cephalosporin ◽  
Fecal Microbiota ◽  
Metagenomic Sequencing ◽  
Gut Dysbiosis ◽  
Prosthetic Joint ◽  
The Impact

Abstract Background There is growing interest about the deleterious impact of antibiotics on loss of gut symbiosis, called dysbiosis. As patients with BJI require antibiotics usually during 6 to 12 weeks, it is of interest to determine whether dysbiosis is frequent in this population, and if it could potentially reversible or not. Methods Multicentric prospective cohort study in France (EudraCT 2016-003247-10) including patients with 3 categories of BJI: native, osteosynthesis-related and prosthetic joint infection (PJI). At the time of suspicion (V1), at the end of therapy (V2) and then 2 weeks after stopping therapy (V3), blood and fecal samples were collected. Extracted DNA from stool was sequenced using shotgun metagenomic sequencing based on illumina library and Iseq instrumentation. Data run through a dedicated pipeline in order to produce microbiome indexes such as Sympson or Shannon diversities indexes. Gut microbiome and inflammation markers were analyzed including fecal neopterin, a maker of gut inflammation. Results Concerning the 62 patients included (mean age, 60 years; mean duration of antibiotics, 66 days), 27 had native, 14 had osteosynthesis and 21 had PJI. The most frequently prescribed drug was a fluoroquinolone, followed by a third-generation cephalosporin and vancomycin. Stools from 42 of them were analyzed as per protocol. Overall, the mean Shannon richness index decreased from 0.904 at V1 to 0.845 at V2; the Bray-Curtis index underlined the difference in microbiome reconstitution at V3 in comparison with V1. We report significant microbiome loss of diversity at V2, that was reversible at V3 in patients with native BJI and osteosynthesis-related BJI, but not in patients with PJI (figure). Fecal neopterin increased between V1 and V2 (mean 221.6 and 698.1 pmol/g of feces, respectively) and then decreased at V3 (422.5 pmol/g), and could be a potential surrogate marker of gut dysbiosis. Of note, patients with abnormal CRP at the end of antibiotics had high neopterin values, that raises the hypothesis that abnormal CRP at the end of antibiotics could be in relation with gut dysbiosis rather than uncured BJI. Conclusion The impact of antibiotics on the gut microbiota of patients with BJI seems to be significant, especially in patients with PJI who could be candidate for fecal microbiota transplantation. Disclosures All authors: No reported disclosures.

Assessment of extracellular matrix and tissue derived metabolites in a liquid biopsy for identifying endotypes of metastatic melanoma patients with differential response to immune checkpoint inhibitor treatment.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14050-e14050
Author(s):  
Nicholas Willumsen ◽  
Cecilie Liv Bager ◽  
Christina Jensen ◽  
Morten Asser Karsdal ◽  
Daniel Hargbøl Madsen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Metastatic Melanoma ◽  
Cancer Patients ◽  
Hierarchical Clustering ◽  
Immune Checkpoint ◽  
Liquid Biopsy ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Ecm Remodeling

e14050 Background: The extracellular matrix (ECM) is a major component of tumors. Several recent findings link ECM composition with outcome in cancer patients treated with immune checkpoint inhibitors (ICIs). The aim here was to explore circulating ECM- and tissue-derived metabolites to enable clustering of patients with metastatic melanoma (MM) into putative endotypes and evaluate patient characteristics and outcome when treated with Ipilimumab accordingly. Methods: Serum was collected from MM patients prior to treatment with Ipilimumab (n = 64). Wards hierarchical clustering of patients was based on 15 ECM- and tissue-derived metabolites measured in serum by ELISA. Identified clusters (endotypes) were compared to clinical characteristics and evaluated for associations with disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: Three putative endotypes (cluster A, B, C) were identified including 14, 30 and 20 patients, respectively. Overall a stepwise increase in ECM metabolite median levels were detected from C-B-A with the largest absolute change seen from B-A. There was no difference between A, B, and C according to age, gender, lactate dehydrogenase levels, number of metastasized organs and whether patients were treated previously. At follow-up, the DCR was 0%, 60% and 45% in A, B, and C, respectively. Likewise, patients with endotype A had a median PFS/OS time of 69/85 days versus 174/520 and 165/589 days for endotype B and C. In support, endotype A predicted for poor survival outcomes (PFSAvsB+C:HR = 3.9, 95%CI:2.0-7.6, p = 0.0001; OSAvsB+C:HR:2.5, 95%CI:1.2-4.9, p = 0.0108). Conclusions: Hierarchical clustering of MM patients based on 15 ECM- and tissue-derived metabolites measured in a liquid biopsy identifies 3 putative endotypes. One endotype (A) seems to reflect patients with an overall high and differentiated ECM turnover profile. These patients experience poor outcome when treated with Ipilimumab. If validated, this supports a link between ECM remodeling and outcome in cancer patients treated with ICIs.

scholarly journals The Role of Gut Microbiota in Lung Cancer: From Carcinogenesis to Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiangjun Liu ◽  
Ye Cheng ◽  
Dan Zang ◽  
Min Zhang ◽  
Xiuhua Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Fecal Microbiota Transplantation ◽  
Checkpoint Inhibitors ◽  
Fecal Microbiota ◽  
Immune Homeostasis ◽  
Gut Dysbiosis ◽  
Underlying Mechanisms ◽  
And Function

The influence of microbiota on host health and disease has attracted adequate attention, and gut microbiota components and microbiota-derived metabolites affect host immune homeostasis locally and systematically. Some studies have found that gut dysbiosis, disturbance of the structure and function of the gut microbiome, disrupts pulmonary immune homeostasis, thus leading to increased disease susceptibility; the gut-lung axis is the primary cross-talk for this communication. Gut dysbiosis is involved in carcinogenesis and the progression of lung cancer through genotoxicity, systemic inflammation, and defective immunosurveillance. In addition, the gut microbiome harbors the potential to be a novel biomarker for predicting sensitivity and adverse reactions to immunotherapy in patients with lung cancer. Probiotics and fecal microbiota transplantation (FMT) can enhance the efficacy and depress the toxicity of immune checkpoint inhibitors by regulating the gut microbiota. Although current studies have found that gut microbiota closely participates in the development and immunotherapy of lung cancer, the mechanisms require further investigation. Therefore, this review aims to discuss the underlying mechanisms of gut microbiota influencing carcinogenesis and immunotherapy in lung cancer and to provide new strategies for governing gut microbiota to enhance the prevention and treatment of lung cancer.

scholarly journals Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management

2019 ◽  
Vol 12 ◽  
pp. 175628481988419 ◽  
Author(s):  
Uday N. Shivaji ◽  
Louisa Jeffery ◽  
Xianyong Gui ◽  
Samuel C. L. Smith ◽  
Omer F. Ahmad ◽  
...  
Keyword(s):  
Early Intervention ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Management Strategies ◽  
Intestinal Barrier ◽  
Common Side Effect ◽  
Drug Induced ◽  
Immune Balance ◽  
Steroid Refractory

Background: Drug-induced colitis is a known complication of therapies that alter the immune balance, damage the intestinal barrier or disturb intestinal microbiota. Immune checkpoint inhibitors (ICI) directed against cancer cells may result in activated T lymphocyte-induced immune-related adverse events (AEs), including immune-related colitis and hepatitis. The aim of this review article is to summarize the incidence of gastrointestinal (GI) and hepatic AEs related to ICI therapy. We have also looked at the pathogenesis of immune-mediated AEs and propose management strategies based on current available evidence. Methods: A literature search using PubMed and Medline databases was undertaken using relevant search terms pertaining to names of individual drugs, mechanism of action, related AEs and their management. Results: ICI-related GI AEs are common, and colitis appears to be the most common side effect, with some studies reporting incidence as high as 30%. The incidence of both all-grade colitis and hepatitis were highest with combination therapy with anti-CTLA-4/PD-1; severity of colitis was dose-dependent (anti-CTLA-4). Early intervention is associated with better outcomes. Conclusion: ICI-related GI and hepatic AEs are common and clinicians need to be aware. Patients with GI AEs benefit from early diagnosis using endoscopy and computed tomography. Early intervention with oral steroids is effective in the majority of patients, and in steroid-refractory colitis infliximab and vedolizumab have been reported to be useful; mycophenolate has been used for steroid-refractory hepatitis.

scholarly journals The Role of Molecular Profiling to Predict the Response to Immune Checkpoint Inhibitors in Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 201 ◽  
Author(s):  
Courèche Kaderbhaï ◽  
Zoé Tharin ◽  
François Ghiringhelli
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Surrogate Marker ◽  
Dna And Rna ◽  
Tumor Mutational Burden ◽  
Tumor Expression

Immune checkpoint inhibitors radically changed the treatment of patients with non-small cell lung cancer (NSCLC). However, only one-quarter of patients benefit from these new therapies when used as monotherapy. The assessment of Program Death Ligand-1 (PD-L1) tumor expression by immunohistochemistry is used to select potential responder patients, but this not an optimal marker since it does not predict the absence of anti PD-1 efficacy. Despite this shortcoming, PD-L1 remains the gold standard biomarker in many studies and the only biomarker available for clinicians. In addition to histological markers, transcriptomic and exome analyses have revealed potential biomarkers requiring further confirmation. Recently, tumor mutational burden has emerged as a good surrogate marker of outcome. In this review we will detail current knowledge on DNA and RNA related biomarkers.

scholarly journals The Challenge of ICIs Resistance in Solid Tumours: Could Microbiota and Its Diversity Be Our Secret Weapon?

2021 ◽  
Vol 12 ◽  
Author(s):  
Michela Roberto ◽  
Catia Carconi ◽  
Micaela Cerreti ◽  
Francesca Matilde Schipilliti ◽  
Andrea Botticelli ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Human Body ◽  
Fecal Microbiota Transplantation ◽  
Checkpoint Inhibitors ◽  
Fecal Microbiota ◽  
Dietary Factors ◽  
Human Microbiota ◽  
Sequencing Technologies ◽  
And Function ◽  
Cancer Immunotherapies

The human microbiota and its functional interaction with the human body were recently returned to the spotlight of the scientific community. In light of the extensive implementation of newer and increasingly precise genome sequencing technologies, bioinformatics, and culturomic, we now have an extraordinary ability to study the microorganisms that live within the human body. Most of the recent studies only focused on the interaction between the intestinal microbiota and one other factor. Considering the complexity of gut microbiota and its role in the pathogenesis of numerous cancers, our aim was to investigate how microbiota is affected by intestinal microenvironment and how microenvironment alterations may influence the response to immune checkpoint inhibitors (ICIs). In this context, we show how diet is emerging as a fundamental determinant of microbiota’s community structure and function. Particularly, we describe the role of certain dietary factors, as well as the use of probiotics, prebiotics, postbiotics, and antibiotics in modifying the human microbiota. The modulation of gut microbiota may be a secret weapon to potentiate the efficacy of immunotherapies. In addition, this review sheds new light on the possibility of administering fecal microbiota transplantation to modulate the gut microbiota in cancer treatment. These concepts and how these findings can be translated into the therapeutic response to cancer immunotherapies will be presented.

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