Immune-mediated Colitis Research Articles

Checkpoint Inhibitor-Induced Colitis.

Immune checkpoint inhibitors have revolutionized treatment and overall survival for several different types of cancer. Antibodies to cytotoxic T-lymphocyte-associated protein 4 and to programmed cell death protein 1 and its ligand enhance cytotoxic T-cell survival, thus augmenting antitumor action and consequently inducing immune-related adverse events, of which the most relevant is diarrhea and colitis. This review compiles recent data on pathophysiology, clinical manifestations, and treatment of immune-mediated colitis (IMC). The pathogenesis of IMC is not completely understood, but recent studies have focused on the role of regulatory T cells and interactions with the gut microbiome. While sharing similarities with inflammatory bowel disease, IMC is considered a distinct form of colitis with acute onset and rapid progression leading to potential complications including bowel perforation and death. Prompt recognition and management of IMC is imperative for optimal outcomes. Although prospective clinical trials are lacking to guide therapy, recent guidelines recommend early endoscopic evaluation to establish the diagnosis and prompt initiation of corticosteroids. Response to first-line therapy should be assessed early to determine the need of escalation to biologic agents. With treatment, most patients will experience full resolution of symptoms, and subsequent rechallenge with anti-programmed cell death protein 1 or anti-programmed death-ligand 1 inhibitors can be considered.

From This Month's Histopathology

From This Month's Histopathology

P040 Is Vedolizumab the Answer to Decreasing the Incidence of Immune-Mediated Colitis in Patients With Pre-Existing Inflammatory Bowel Disease?

P040 Is Vedolizumab the Answer to Decreasing the Incidence of Immune-Mediated Colitis in Patients With Pre-Existing Inflammatory Bowel Disease?

1570 A Less Recognized Cause of Checkpoint Inhibitor-Induced Diarrhea

INTRODUCTION: Immune checkpoint inhibitors (ICPIs) are increasingly being used for the treatment of a number of malignancies. These immunomodulatory antibodieshave substantially improved the prognosis for patients with advanced cancers. ICPIs have been associated with immune-mediated colitis causing diarrhea and often hematochezia, with significant inflammation on endoscopic evaluation. We present an unexpected adverse event in a patient being treated with an ICPI. CASE DESCRIPTION/METHODS: A 58-year-old male with stage-4 lung adenocarcinoma, on pembrolizumab presented with abdominal pain, nausea and diarrhea. His symptoms had been ongoing for 6 months. He endorsed 10 lb weight loss over two months. He had completed his 22nd cycle of pembrolizumab 1 week prior to presentation. On examination, he was tachycardic and had mild tenderness in bilateral lower quadrants. Labs revealed Hgb of 19 g/dl, BUN 26, with a mild hyponatremia. He had mild leukocytosis and a CRP of 73.8 mg/L. Infectious work up was negative and the patient started loperamide. Colonoscopy revealed a normal appearing mucosa without evidence of mucosal inflammation or ulceration. Pembrolizumab was held and he was started on IV methylprednisolone with improvement in the frequency of his bowel movement. He was discharged home on an oral prednisone. Pathology from the random biopsies demonstrated surface epithelial damage with increased intraepithelial lymphocytes without significant crypt distortion, consistent with lymphocytic colitis. The patient was switched from prednisone to budesonide because of the lower rate of response associated with prednisone. He completed a taper with resolution of his symptoms. DISCUSSION: ICPIs are associated with a unique spectrum of side effects termed immune-related adverse events. Diarrhea is a common clinical complaint in patients this patient population, with immune-mediated colitis being a common cause. Typically endoscopic and histopathological features of immune checkpoint inhibitor-induced colitis are similar to inflammatory bowel disease (IBD) flare rather than microscopic colitis as seen in this case. The data on clinical, endoscopic, and histologic characteristics as well as management strategies for immune checkpoint induced microscopic colitis, is limited. Our case, suggests a unique form of gastrointestinal toxicity associated with pembrolizumab (PD-1 blocker) and highlights successful management with IV and oral corticosteroids, which permitted the patient to continue pembrolizumab without interruption.

1503 A Rare Case of Nivolumab-Induced Early Onset Immune-Mediated Colitis With Normal Appearing Mucosa

INTRODUCTION: Programmed Cell Death Protein 1 (PD-1) inhibitor, nivolumab, is increasingly being used for the treatment of advanced neoplasms including melanoma, renal and metastatic lung cancers. Side effects of nivolumab include Immune-mediated colitis (IMC) with a median time to onset between 6-18 weeks. We present a patient with adenocarcinoma of the lung who developed IMC within a week of initiation of nivolumab. CASE DESCRIPTION/METHODS: A 75-year old male with a history of recurrent stage IIIA adenocarcinoma of lung presented with a one-week history of 5-6 non-bloody liquid bowel movements (grade 2 colitis) with nocturnal episodes. His symptoms started within a week of initiation of nivolumab. The patient had persistent diarrhea despite overnight fast and had associated severe abdominal cramps and nausea. His vital signs were stable on presentation and physical exam was significant for clinical dehydration and tenderness to palpation in the LLQ. CT A/P and AXR were unremarkable while infectious workup including C. Difficile was negative. His stool guaiac, fecal elastase, and serum lipase were negative while his inflammatory markers including ESR, CRP and fecal calprotectin (193 μg/g) were elevated. A colonoscopy was performed which showed normal appearing mucosa while random colon biopsy demonstrated increased intra-epithelial lymphocytes, surface epithelial injury, expansion of lamina propria by mononuclear inflammatory infiltrate and scattered crypt abscesses. CMV immunochemical stain was negative. Nivolumab was discontinued following biopsy result and the patient was started on oral prednisone 40 mg bid with the resolution of diarrhea within 2 weeks of treatment. He was later transitioned to oral budesonide. DISCUSSION: IMC is more commonly seen with Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) inhibitors as opposed to PD-1 inhibitors especially nivolumab. Although the average time of onset of nivolumab associated colitis ranges between 6-18 weeks, early onset IMC is rare but possible as in our case. IMC can have an atypical presentation with early onset diarrhea and normal appearing mucosa as in our case. Clinicians need to have a high index of suspicion for IMC while taking care of patients receiving PD-1 inhibitors presenting with diarrhea or abdominal pain.

1501 Double Whammy: Checkpoint Inhibitor and CMV-Induced Colitis

INTRODUCTION: Immune checkpoint inhibitors (ICIs) such as nivolumab have become a common treatment for several types of malignancies, especially metastatic disease. Diarrhea and enterocolitis are known side effects of these drugs. Here we present a case of a patient who developed ICI associated colitis who was later diagnosed with superimposed Cytomegalovirus colitis. CASE DESCRIPTION/METHODS: A 75-year-old male with past medical history pertinent for squamous cell carcinoma of the neck and base of tongue treated with nivolumab. His treatment was interrupted due to the development of chronic diarrhea possibly related to immune checkpoint inhibitor therapy (nivolumab). Immunotherapy was discontinued and the patient was started on a high dose of steroids with initial clinical response and symptom control. He was admitted to the hospital two months later with signs of shock with hematochezia and profound diarrhea. Computed Tomography (CT) of his abdomen upon admission showed severe colitis. Blood cultures were positive for Streptococcus infantarium (previously known as Streptococcus bovis) likely translocation from severe immunotherapy-induced colitis. His hemodynamics improved with fluid resuscitation and antibiotic therapy; however his diarrhea did not resolve. He then underwent colonoscopy which demonstrated circumferential, uninterrupted, extensive and severe inflammation (Figures 1 and 2) with the procedure terminated prematurely to avoid risk of perforation. Pathology of colonic biopsies showed positive immunostaining for Cytomegalovirus (CMV), and the patient tested positive for CMV DNA PCR, confirming acute active infection. He was started on valganciclovir and his steroid regimen was tapered with significant improvement of his diarrhea. DISCUSSION: Immune checkpoint inhibitors are monoclonal antibodies that target downregulators of the anti-neoplastic immune response. There are currently seven FDA approved ICIs, including Nivolumab. Immune-mediated colitis and diarrhea are the most common side effects associated with these drugs. One third of patients treated with ICIs will experience gastrointestinal adverse effects and 1-2% of patients on nivolumab will experience diarrhea. Although is not common, infection can coexist and in the setting of persistent and recurrent diarrhea it has to be ruled out.

1658 Colonic Metastatic Disease Masquerading as Immune Checkpoint Inhibitor-Mediated Colitis

INTRODUCTION: The use of immune-checkpoint inhibitors (ICIs) in the treatment of advanced cancer has increased exceptionally since ipilimumab was first approved for melanoma in 2011. As the prevalence of patients being treated with ICIs rises so too have their immune related adverse events (irAEs). Clinicians are now faced with the challenge of accurately and promptly recognizing irAEs. With immune-mediated diarrhea and colitis being two of the most common irAEs, an algorithm for their treatment has already been established; however, it is important for clinicians to maintain a broad differential diagnosis when caring for a patient on an ICI with colitis symptoms. CASE DESCRIPTION/METHODS: A 48-year-old woman with a history of metastatic, refractory, triple negative, BRCA positive breast cancer was started on pembrolizumab four years after being diagnosed with breast cancer. 18 months after initiating treatment with pembrolizumab, she developed loose, watery stools. Cross sectional imaging revealed mild, circumferential wall thickening of the proximal ascending colon. A gastrointestinal pathogen nucleic acid detection test was negative, and she was started on a two-week course of budesonide for presumed immune checkpoint inhibitor-mediated colitis (IMC). Her symptoms progressed with bright red blood per rectum and abdominal cramping. Treatment for IMC was escalated with a prednisone taper followed by infliximab infusion. 6 weeks after being treated for IMC, her hemoglobin was 7.6 and ferritin 4. She was referred to gastroenterology for iron deficiency anemia. Repeat abdominal CT revealed increased colonic wall thickening. Colonoscopy revealed an obstructing, ulcerated mass in the ascending colon. Pathology identified poorly differentiated adenocarcinoma consistent with a breast cancer metastasis. She underwent right hemicolectomy 6 months after the initial CT showed colonic thickening. DISCUSSION: Pembrolizumab is one of many ICIs that have been developed for the treatment of advanced-stage malignancies. The gastrointestinal side effects of this class of medications pose a challenge for physicians as IMC is nearly indistinguishable from many other etiologies of diarrhea clinically, and the onset of gastrointestinal symptoms ranges widely from 1 to 32 weeks after starting the medication. As the use of ICIs becomes more widespread, quick and accurate differentiation of an irAE from other life threatening pathology is of vital importance, and early colonoscopy should be considered to rule out metastatic disease.

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

As the use of immune checkpoint inhibitors for several different malignancies becomes more mainstream, their side-effect profile raises new challenges. In 2011, the Food and Drug Administration approved the first checkpoint inhibitor for the treatment of advanced melanoma, and since then, checkpoint inhibitors have demonstrated efficacy in many other tumor types. Given the frequent use of immune checkpoint inhibitors in a wide range of cancers today, the diagnosis and management of their immune-mediated toxicities need special attention. One of the most common is immune-mediated colitis. Workup and management of immune-mediated colitis can be challenging and is the purpose of this review. KEY POINTS: Rate of immune mediated colitis differ from different kind of immune checkpoint inhibitor treatment. To work up immune-mediated colitis, tests to rule out infectious etiologies of diarrhea, colonoscopy and abdominal image will help to differentiate immune mediated colitis from colitis from other etiology. Patients with mild colitis can be managed with supportive therapies alone, but more severe cases may require immunomodulators such as steroid. Refractory cases may require tumor necrosis factor (TNF) inhibitors, such as infliximab in addition to steroid treatment.

Clinical Variables as Predictors of First Relapse in Pediatric Crohn's Disease.

IntroductionCrohn's disease (CD) is an immune-mediated inflammatory bowel disease (IBD) that can affect any portion of the gastrointestinal tract from the mouth to the anus. The clinical course of CD is characterized by periods of symptomatic relapse and remission. Clinical variables may identify a subset of patients with CD at risk for relapse. Identifying these patients, and early stratification-based treatment would be of utmost clinical importance in optimizing the management and is likely to improve long-term disease outcome. In pediatric-onset IBD there is a paucity of data for predicting clinical behavior and results are conflicting. With this background, we hypothesized that routinely measured clinical variables at the time of diagnosis would predict relapse in patients with CD, and sought to investigate the clinical predictors of relapse present at the time of diagnosis in our patient population. We further compared differences in clinical variables and laboratory values for patients who relapsed early, compared with those who relapsed late.MethodsWe conducted a retrospective chart review of patients diagnosed with CD by clinical, radiological, endoscopic and histological criteria at St. John Providence Children’s Hospital pediatric GI clinic between 01/2006 and 12/2014. Patients were followed until they had their first relapse or for three years from diagnosis, whichever was earlier. Variables studied included demographic factors (age, gender, race, BMI, BMI percentiles and family history of IBD), presenting symptoms (blood in stools, nocturnal stools, fever, and extra-intestinal manifestations), phenotypic characteristics (using Montreal classification), and laboratory data [white blood cell (WBC) count, hemoglobin, hematocrit, platelet count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)].ResultsTwenty-nine patients were included in the study. One was lost to follow up, and 28 were included in the analyses. The relapse rate was 50% at three years, and 32% patients relapsed within one year of diagnosis. Low BMI percentile at diagnosis (41.5 ± 28.8 vs. 18.0 ± 20.3; p-value 0.03) was a predictor of relapse. Comparing early relapse to those who relapsed late, there were no statistically significant differences between the two groups.ConclusionsLow BMI percentile at presentation was associated with increased risk of relapse, suggesting that routinely measured clinical variables may have role in predicting first relapse in this patient population. There was no significant difference in the variable comparing patients who relapsed early vs. those who relapsed late. Future prospective studies with larger sample sizes need to be done to predict relapse.

Complex Bacterial Consortia Reprogram the Colitogenic Activity of Enterococcus faecalis in a Gnotobiotic Mouse Model of Chronic, Immune-Mediated Colitis.

Inflammatory bowel diseases (IBD) are associated with compositional and functional changes of the intestinal microbiota, but specific contributions of individual bacteria to chronic intestinal inflammation remain unclear. Enterococcus faecalis is a resident member of the human intestinal core microbiota that has been linked to the pathogenesis of IBD and induces chronic colitis in susceptible monoassociated IL-10-deficient (IL-10−/−) mice. In this study, we characterized the colitogenic activity of E. faecalis as part of a simplified human microbial consortium based on seven enteric bacterial strains (SIHUMI). RNA sequencing analysis of E. faecalis isolated from monoassociated wild type and IL-10−/− mice identified 408 genes including 14 genes of the ethanolamine utilization (eut) locus that were significantly up-regulated in response to inflammation. Despite considerable up-regulation of eut genes, deletion of ethanolamine utilization (ΔeutVW) had no impact on E. faecalis colitogenic activity in monoassociated IL-10−/− mice. However, replacement of the E. faecalis wild type bacteria by a ΔeutVW mutant in SIHUMI-colonized IL-10−/− mice resulted in exacerbated colitis, suggesting protective functions of E. faecalis ethanolamine utilization in complex bacterial communities. To better understand E. faecalis gene response in the presence of other microbes, we purified wild type E. faecalis cells from the colon content of SIHUMI-colonized wild type and IL-10−/− mice using immuno-magnetic separation and performed RNA sequencing. Transcriptional profiling revealed that the bacterial environment reprograms E. faecalis gene expression in response to inflammation, with the majority of differentially expressed genes not being shared between monocolonized and SIHUMI conditions. While in E. faecalis monoassociation a general bacterial stress response could be observed, expression of E. faecalis genes in SIHUMI-colonized mice was characterized by up-regulation of genes involved in growth and replication. Interestingly, in mice colonized with SIHUMI lacking E. faecalis enhanced inflammation was observed in comparison to SIHUMI-colonized mice, supporting the hypothesis that E. faecalis ethanolamine metabolism protects against colitis in complex consortia. In conclusion, this study demonstrates that complex bacterial consortia interactions reprogram the gene expression profile and colitogenic activity of the opportunistic pathogen E. faecalis toward a protective function.

Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis.

PURPOSEImmune checkpoint inhibitor (ICI) therapy often is suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the rate of and risk factors for IMDC recurrence after ICI resumption.METHODSThis retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between January 2010 and November 2018. Univariable and multivariable logistic regression analyses assessed the association of clinical covariates and IMDC recurrence.RESULTSOf the 167 patients in our analysis, 32 resumed an anti–cytotoxic T-cell lymphocyte-4 (CTLA-4) agent, and 135 an anti–programmed cell death 1 or ligand 1 (PD-1/L1) agent. The median age was 60 years (interquartile range [IQR], 50-69 years). The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136 days). IMDC recurred in 57 patients (34%) overall (44% of those receiving an anti–CTLA-4 and 32% of those receiving an anti–PD-1/L1); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC, and all required permanent discontinuation of ICI therapy. The median duration from ICI resumption to IMDC recurrence was 53 days (IQR, 22-138 days). On multivariable logistic regression, patients who received anti–PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45; 95% CI, 1.59 to 7.69; P = .002). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95% CI, 1.08 to 9.62; P = .019) or had a longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95% CI, 1.00 to 1.03; P = .031). Risk of IMDC recurrence was lower after resumption of anti–PD-1/L1 therapy than after resumption of anti–CTLA-4 therapy (OR, 0.30; 95% CI, 0.11 to 0.81; P = .019).CONCLUSIONOne third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. Recurrence of IMDC was less frequent after resumption of anti–PD-1/L1 than after resumption of anti–CTLA-4.

Outcomes after early initiation of nonsteroidal immunosuppressive therapy in patients with immune checkpoint inhibitor-induced colitis.

2571 Background: Current treatment guidelines for immune-mediated colitis (IMC) recommend 4 to 6 weeks of steroids as first-line therapy, followed by nonsteroidal immunosuppressive therapy (NSIST) (infliximab or vedolizumab) in patients who do not respond to steroids. We assessed the effect of early NSIST introduction and number of NSIST infusions on clinical outcomes. Methods: We performed a retrospective review of patients with IMC who received NSIST between January and December 2018. Logistic regression analyses were used to assess associations between clinical features and outcomes of IMC (Table). Results: Of the 1,459 patients who received immune checkpoint inhibitor, 179 developed IMC of any grade; 84 of them received NSIST. Of the 84 patients who received NSIST, 79% were males with mean age of 60. Compared with patients who received NSIST >10 days after IMC onset, patients who received early NSIST (≤10 days) required fewer hospitalizations ( P=0.03), experienced steroid taper failure less frequently ( P=0.03), had fewer steroid tapering attempts ( P<0.01), had a shorter course of steroid treatment ( P=0.09), and had a shorter duration of symptoms ( P<0.01). Risk factors of IMC recurrence after weaning off steroids included: 1) needing multiple hospitalizations ( P<0.01), 2) experiencing steroid taper failure after NSIST ( P=0.02), 3) receiving infliximab rather than vedolizumab ( P=0.02), 4) receiving fewer than three infusions of NSIST ( P=0.02), 5) having higher fecal calprotectin levels after NSIST ( P=0.01), and 6) receiving a longer course of steroids ( P=0.02), hospitalization ( P<0.01) and IMC symptoms ( P<0.01). Unsuccessful weaning from steroids after NSIST was associated with high IMC grades ( P<0.01); multiple hospitalizations ( P<0.01); steroid-resistant IMC ( P<0.01); long interval from IMC to NSIST initiation ( P=0.01); and long duration of steroids ( P<0.01), IMC symptoms ( P<0.01), and hospitalization ( P<0.01). Conclusions: NSIST should be introduced early in the disease course of IMC instead of waiting until failure of steroid therapy or steroid taper. Patients who received three or more infusions of NSIST had more favorable clinical outcomes.

Immune-mediated colitis after resumption of immune checkpoint inhibitor therapy.

2577 Background: Immune checkpoint inhibitor (ICI) therapy is often suspended because of immune-mediated diarrhea and colitis (IMDC). We examined the recurrence rate and risk factors for IMDC after ICI resumption. Methods: This retrospective multicenter study examined patients who resumed ICI therapy after improvement of IMDC between 1/2010 and 11/2018. Univariate and multivariate logistic regression analyses assessed the association of clinical covariates and IMDC recurrence. Results: Of the 167 patients in our analysis, 32 resumed an anti-CTLA-4 agent and 135 an anti-PD-1/L1 agent. The median duration from IMDC to restart of ICI treatment was 49 days (IQR, 23-136). IMDC recurred in 57 (34%) patients overall (44% of those resuming an anti–CTLA-4 and 32% resuming an anti–PD-1/L1 agent); 47 of these patients (82%) required immunosuppressive therapy for recurrent IMDC (Table). The median duration from ICI resumption to IMDC recurrence was 53 days (IQR 22-138). On multivariate logistic regression, patients who received anti-PD-1/L1 therapy at initial IMDC had a higher risk of IMDC recurrence (odds ratio [OR], 3.45, 95%CI, 1.59-7.69; P<0.01). Risk of IMDC recurrence was higher for patients who required immunosuppression for initial IMDC (OR, 3.22; 95%CI, 1.08-9.62; P=0.02) or had longer duration of IMDC symptoms in the initial episode (OR, 1.01; 95%CI, 1.00-1.03; P=0.03). Risk of IMDC recurrence was lower for those who resumed anti–PD-1/L1 therapy than for those who resumed anti–CTLA-4 therapy (OR, 0.30; 95%CI, 0.11-0.81; P=0.02). Conclusions: One-third of patients who resumed ICI treatment after IMDC experienced recurrent IMDC. IMDC recurrence was less frequent after resumption of anti–PD-1/L1 than after anti–CTLA-4. Characteristics of recurrent IMDC based on resumed ICI therapy. [Table: see text]

Systematic review and case series: flexible sigmoidoscopy identifies most cases of checkpoint inhibitor-induced colitis.

Immune checkpoint inhibitors are used in the treatment of multiple advanced stage cancers but can induce immune-mediated colitis necessitating treatment with immunosuppressive medications. Diagnostic colonoscopy is often performed but requires bowel preparation and may delay diagnosis and treatment. Sigmoidoscopy can be performed rapidly without oral bowel preparation or sedation. Characterize the colonic distribution of immune-mediated colitis to determine the most efficient endoscopic approach. A systematic review of checkpoint inhibitor-induced colitis case reports and series was conducted in both PubMed and Embase through 3 January 2017. A single centre retrospective chart review of patients who underwent endoscopic evaluation for diarrhoea after treatment with a checkpoint inhibitor (ipilimumab, nivolumab or pembrolizumab) between 1 January 2011 and 3 January 2017 was performed. Clinical, endoscopic and histologic data were collected. A detailed systematic review resulted in 61 studies, in which 226 cases of colitis were diagnosed by lower endoscopy (125 colonoscopy, 101 sigmoidoscopy). Only four patients had isolated findings proximal to the left colon. In our centre, 31 patients had histologic features of checkpoint inhibitor-induced colitis, for which 29 patients had complete data. The left colon was involved in all cases. Sigmoidoscopy would be sufficient to diagnose >98% of reported cases of checkpoint inhibitor-mediated colitis diagnosed by lower endoscopy. Moderate to severe checkpoint inhibitor-induced colitis involves the left colon in the majority of cases (>98%). Sigmoidoscopy should be the initial endoscopic procedure in the evaluation of this condition.

Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor\u2013induced colitis

BackgroundCurrent treatment guidelines for immune-mediated colitis (IMC) recommend 4 to 6 weeks of steroids as first-line therapy, followed by selective immunosuppressive therapy (SIT) (infliximab or vedolizumab) in patients who do not respond to steroids. We assessed the effect of early SIT introduction and number of SIT infusions on clinical outcomes.MethodsWe performed a retrospective review of patients with IMC who received SIT at The University of Texas MD Anderson Cancer Center between January and December 2018. Logistic regression analyses were used to assess associations between clinical outcomes and features of IMC.ResultsOf the 1459 patients who received immune checkpoint inhibitors, 179 developed IMC of any grade; 84 of these 179 patients received SIT. Of the 84 patients who received SIT, 79% were males, and the mean age was 60 years (standard deviation, 14). Compared with patients who received SIT > 10 days after IMC onset, patients who received early SIT (≤10 days) required fewer hospitalizations (P = 0.03), experienced steroid taper failure less frequently (P = 0.03), had fewer steroid tapering attempts (P < 0.01), had a shorter course of steroid treatment (P = 0.09), and had a shorter duration of symptoms (P < 0.01). Patients who received one or two infusions of SIT achieved histologic remission less frequently (P = 0.09) and had higher fecal calprotectin levels after SIT (P = 0.01) compared with patients who received three or more infusions. Risk factors for IMC recurrence after weaning off steroids included: 1) needing multiple hospitalizations, 2) experiencing steroid taper failure after SIT, 3) receiving infliximab rather than vedolizumab, 4) receiving fewer than three infusions of SIT, 5) having higher fecal calprotectin levels after SIT, and 6) receiving a longer course of steroids, hospitalization and IMC symptoms. Unsuccessful weaning from steroids after SIT was associated with high IMC grades; multiple hospitalizations; steroid-resistant IMC; long interval from IMC to SIT initiation; and long duration of steroids, IMC symptoms, and hospitalization.ConclusionSIT should be introduced early in the disease course of IMC instead of waiting until failure of steroid therapy or steroid taper. Patients who received three or more infusions of SIT had more favorable clinical outcomes.

Immune checkpoint inhibitor-induced colitis: A comprehensive review.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target down-regulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1. ICIs have revolutionized the treatment of a variety of malignancies. However, many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis (IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease, however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.

Impact of the gut microbiota on immune checkpoint inhibitor-associated toxicities.

Immune checkpoint inhibitors (ICIs) have transformed the treatment of patients with advanced cancers. However, the majority of patients do not respond or develop early progressive disease. A substantial number also develop immune-mediated toxicities that may lead to early treatment discontinuation. Gastrointestinal toxicities in the form of diarrhea and colitis are common and may resemble that observed in patients with inflammatory bowel disease (IBD). Alterations in the gut microbiota are thought to play an important role in mediating the intestinal inflammation that is associated with immune-mediated colitis. In this review, the authors’ objective is to provide an overview of the gastrointestinal and hepatic toxicities that can be seen with ICIs and discuss the interactions between gut microbiota and the immune response. The authors also highlight the potential role for fecal microbial transfer (FMT) as an approach to improve therapeutic efficacy and decrease toxicity.

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

ABSTRACTWe report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.

Abstract LB-151: Prophylactic TNFα blockade unplugs toxicity and efficacy in immunotherapy anti-PD-1 + anti-CTLA-4 combinations

Abstract The combination of anti-CTLA-4 and anti-PD-1 checkpoint inhibitors ipilimumab and nivolumab (DIT) has improved survival of patients with metastatic melanoma and renal cell carcinoma in exchange for frequent immune-mediated serious side effects (mainly gastrointestinal), leading to treatment cessation in about one third of the patients and the need to reduce doses of these immunotherapy agents when used in combination. Tumor necrosis factor-α (TNF-α) is an important actionable mediator in inflammatory bowel disease (both ulcerative colitis and Crohn's disease) and its blockade with monoclonal antibodies has been recommended to treat steroid-resistant colitis following checkpoint inhibitors. We have studied whether prophylactic TNFα blockade is able to reduce immune toxicity associated with DIT without altering antitumor activity. Experiments were performed in C57BL/6 mice harboring subcutaneous tumors derived from the MC38 and B16OVA cell lines. Acute immune-mediated colitis was induced by exposure to 3% dextran sulfate sodium (DSS) in drinking water for 3 days. For TNFα blockade etanercept (hTNFR2-IgG chimera) or a mouse anti-TNF-α monoclonal antibody were used. Anti-tumor efficacy was tested following individual tumor sizes upon combined treatment with anti-mPD-1 + anti-mCTLA4 mAbs. Severity of DSS colitis was assessed and scored by daily weight, ultrasound evaluation of intestinal wall thickness and histological assessment on day 7. We observed that the antitumoral efficacy of PD-1+CTLA-4 blockade against MC38 of B16OVA established tumors was not reduced with the prophylactic association of TNF-α blockade. Intriguingly, an improvement of antitumor activity was observed in those mice in which DSS colitis was induced. Importantly, in mice suffering DSS-induced colitis that were co-treated with DIT and TNF-α blockade, digestive toxicity ameliorates as shown by body weight, ultrasound examination and histology. Therefore, TNF-α blockade can be prophylactically associated with anti-PD1 + anti-CTLA-4 mAb combination regimens to prevent toxicity without hindrance of anti-tumor efficacy. These results in mouse models warrant a clinical trial testing profilactic etanercept to improve the safety profile of the nivolumab + ipilimumab combination widening its therapeutic window. Citation Format: ELISABETH PEREZ-RUIZ, LUNA MINUTE, MARIA CARMEN OCHOA, ARANTXA AZPILICUETA, SARAY GARASA, M E RODRIGUEZ-RUIZ, VIRGINIA BELSUE, CARMEN MOLINA, PEDRO BERRAONDO, IGNACIO MELERO. Prophylactic TNFα blockade unplugs toxicity and efficacy in immunotherapy anti-PD-1 + anti-CTLA-4 combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-151.

Risk of immune-related colitis with PD-1/PD-L1 inhibitors vs chemotherapy in solid tumors: systems assessment.

Background: We performed a meta-analysis to evaluate the risk of immune-related colitis associated with PD1/PD-L1 inhibitors as compared to chemotherapy in solid tumor patients.Methods: Eligible studies were identified through a comprehensive search of multiple databases and included solid tumor patients in randomized controlled trials (RCTs) with PD-1/PD-L1 inhibitors. The data was analyzed by Stata version 12.0 software.Results: After exclusion of ineligible studies, 11 clinical trials were considered eligible for the meta-analysis, including 5751 patients. Compared with chemotherapy, the risk ratios (RRs) of all-grade colitis were significant for the PD-1 inhibitor subgroup (RR 2.69, 95% confidence interval (CI): 1.15-6.29, p=0.023), and for pembrolizumab subgroup (RR 3.17, 95% CI: 1.08-9.37, p=0.037), but not for nivolumab treatment and PD-L1 inhibitor (atezolizumab) treatment (RR 2.05, 95% CI: 0.52-8.13, p=0.305; RR 4.75,95% CI: 0.56-40.50, p=0.154, respectively). The RR of all-grade colitis was significant for PD-1/PD-L1 inhibitor in NSCLC (RR 4.34, 95% CI: 1.37-13.82, p=0.013), and not significant in melanoma (RR 2.11, 95% CI: 0.54-8.34, p=0.285). Moreover, the RRs of all-grade diarrhea were significant for the PD-1 inhibitor subgroup (RR 0.61, 95% CI: 0.44-0.83, p=0.002), for the nivolumab subgroup (RR 0.54, 95% CI: 0.34-0.87, p=0.012), and for atezolizumab subgroup (RR 0.48, 95% CI: 0.25-0.89, p=0.021). The RR of high-grade diarrhea was significant for atezolizumab subgroup (RR 0.34, 95% CI: 0.12-0.94, p=0.037).Conclusions: Our meta-analysis demonstrates that compared with chemotherapy, pembrolizumab may result in a higher risk of all-grade immune-mediated colitis. PD-1/PD-L1 inhibitor treatment in NSCLC patients, but not in melanoma patients, increases the risk of all-grade colitis incidence.