Immune checkpoint inhibitor-associated gastrointestinal adverse events in patients with colorectal cancer

Immune checkpoint inhibitor-associated gastrointestinal adverse events in patients with colorectal cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Immune checkpoint inhibitor-associated gastrointestinal adverse events in patients with colorectal cancer Antonio Pizuorno Machado, Malek Shatila, Parvir Aujla, Ryan Huey, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4248366/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Oct, 2023 Read the published version in American Journal of Gastroenterology → Version 1 posted You are reading this latest preprint version Abstract Purpose: Immune checkpoint inhibitors (ICI) are currently employed for the management of microsatellite instability-high (MSI-H) tumors with success. While immune checkpoint inhibitor related colitis is a very frequent and a devastating immune related adverse event (irAE) with the use of these agents, the incidence and characteristics of this inflammatory toxicity in patients with MSI-H colorectal cancers has not been examined. We aimed to describe the characteristics and clinical profile of patients diagnosed with luminal gastrointestinal irAE in patients treated with ICI for colorectal cancer in a tertiary cancer care center. Methods: This is a retrospective analysis that included adult cancer patients diagnosed with colorectal cancer that received ICI between 6/1/2014 and 12/31/2022. We report data on those that developed colitis as an irAE up to 3 months after the last dose of ICI confirmed by laboratory and/or imaging report. We included patients’ demographic characteristics, oncologic profile and outcomes as well as clinical course, endoscopic features as well as treatment and outcomes in terms of luminal gastrointestinal irAEs. Results: Out of 474 patients with colorectal cancer on ICI in our study period, only 18 developed a gastrointestinal irAE with an incidence of 3.8%. Patients were primarily Caucasian (88.8%) males (61.1%) with a median age of 69.5 years. The majority of these patients received combination therapy with anti-PD-1/L1 and CTLA-4 (50%). 66.6 % received ICI for MSI-H colorectal cancer. 11.1% of our sample were noted to have a second cancer-melanoma. The majority of patients had grade 1-2 colitis (61.2%) and grade 1-2 diarrhea (88.8%). Only 5 patients underwent endoscopic evaluation of whom, 2 had ulcerative inflammation necessitating use of selective immunosuppressive therapy with biologics. 61.1% had to withhold cancer treatment due toxicity. With regards to other gastrointestinal irAEs among this population, 41.4% and 5.8% were noted to have liver and pancreas toxicity respectively, with a median CTCAE grade of severity 2. The majority of our cohort received steroids as therapy. Conclusion: Luminal gastrointestinal irAEs seem to occur less frequently and at a lower severity among patients with MSI-H colorectal cancer after checkpoint inhibitors exposure compared to the overall incidence of the same among other cancers reported in literature. Larger prospective studies are necessary to determine the role of tumor biology and the gut microbiome in the disease profile and severity of immune related adverse events of the GI organ system. Immune checkpoint inhibitors Colorectal cancer Immune related adverse event Colitis Figures Figure 1 Introduction Immune checkpoint inhibitors (ICIs) are a potent and increasingly important treatment option for various malignancies. To date, more than eight ICI agents have been approved. While conferring an appreciable survival benefit, these agents also predispose to unique immune-related gastrointestinal adverse events (irAEs), with diarrhea and colitis amongst the most common.[ 1 ] Immune-mediated colitis (IMC) has been reported in up to 40% of patients treated with ICIs. It varies widely in severity[ 2 , 3 ], and can be a cause for discontinuation of ICI therapy[ 4 ]. Failure in early recognition and delayed or suboptimal treatment early in the disease course can lead to an increased risk of complications such as bowel perforation[ 5 ]. The use of ICIs to treat MSI-H colon cancer is a relatively recent advancement. One clinical trial showed pembrolizumab can lead to significantly longer progression-free survival than chemotherapy when received as first-line therapy for microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR)–metastatic colorectal cancer, with fewer treatment-related adverse events[ 6 ]. Several studies have shown activity and clinical benefit for ICIs in colorectal cancer[ 6 – 9 ]. However, much remains to be learned about irAE for this patient population. Given their novelty, our knowledge of their potential irAEs in this setting is still limited. Ostensibly, the presence of malignancy in the bowel may uniquely impact the risk and severity of gastrointestinal irAEs specifically. There have been limited large-scale studies investigating the safety of ICIs in patients with colorectal cancer in terms of irAE. In this retrospective study, we explored the incidence and clinical manifestations of immune-mediated colitis among patients with colorectal cancer. Methods Study design and population This retrospective chart review is a descriptive, single-center study that included adult patients who were diagnosed with colorectal cancer and treated with ICI at a tertiary cancer center between 6/1/2014 and 12/31/2022. This study was approved by the institutional review board with a waiver of patients’ informed consent. We identified adult cancer patients 18 years or older who (1) were treated with ICIs for colorectal cancer, and (2) had a diagnosis of immune-mediated colitis at least 3 months after the last ICI dose. Patients with pre-existing inflammatory bowel disease (IBD), microscopic colitis, or other autoimmune gastrointestinal disorders were excluded. Clinical data Demographic and cancer-related information such as age, gender, primary cancer type, stage, cancer treatments received and doses, and Charlson Comorbidity Index score were collected. Also collected were data related to the onset of colitis, such as date, cycles of ICI before colitis, type of ICI, and peak Common Terminology Criteria for Adverse Events (CTCAE) grades for colitis and diarrhea. Diagnosis of colitis was based on the clinical presentation and endoscopic and histologic features after the exclusion of other etiologies. Information about the treatment for colitis such as steroids, infliximab, and vedolizumab, including doses and start and end dates, was obtained as well. Colonoscopy/sigmoidoscopy and pathology findings at the time of colitis diagnosis were reported if available. Statistical analysis The statistical analyses performed were descriptive in nature. The distributions of continuous variables were summarized by medians and interquartile ranges. The distributions of categorical variables were summarized by frequencies and percentages. These were calculated using SPSS 26. Results Patient population, characteristics and oncologic history We identified 474 patients with diagnosis of CRC that had exposure to ICI between June 2014 and December 2022. Of there, only 18 patients met our inclusion criteria (see patient selection diagram). Included patients had a median age of 69.5 years with 11 patients (61.1%) being female and 16 patients (88.8%) being white ( Table 1 ). As for oncological history, 18 patients (100%) were diagnosed with colorectal cancer, followed by overlapped melanoma in 2 patients (11.1%), genitourinary cancer in 1 patient (5.5%). The majority of the patients (n=13, 72.2%), had stage IV cancer. 12 patients (66.6%) had an MSI-H CRC. With regard to class of ICI that patients received, 9 (50%), 8 (44.4%) and 1 (5.5%) patients received a combination of PD-1/L1 and CTLA-4 combination therapy, PD-1/L1 inhibitor monotherapy and CTLA-4 monotherapy respectively. Patients underwent a median of 6 cycles of ICI. After the colitis event, 5 patients (27.7%) continued with ICI and 2 patients (5.8%) continued with other forms of cancer therapy. Characteristics of colitis The predominant symptom was diarrhea in all 18 patients (100%), and abdominal pain in 18 patients (100%) ( Table 2 ); colitis presented in a median of 259 days after initiating ICI ( Table 1 ). The median fecal calprotectin before treatment was 641mcg/g. Median peak CTCAE of colitis was 1 and for diarrhea was 2 ( Table 2 ). The majority of the patients had grade 1 colitis in 10 patients (55.5%). Hospitalization was required for 4 patients (22.2%). As for the treatment of colitis, steroids were used in the entire cohort, and in conjunction with vedolizumab (1 patient, 5.5%) or infliximab alone (3 patients, 16.6%). Fecal microbiota transplant was performed in 1 patient (5.5%) ( Table 3 ). Endoscopic and histology related characteristics At the time of colitis diagnosis only 5 patients underwent an endoscopic procedure. Non-ulcer inflammation was found in 2 patients (40%), same frequency was seen ulcerative inflammation (2 patients, 40%). On histology, the majority had active inflammation (4 patients, 80%) ( Table 3 ). Discussion This study, to our knowledge is the first to explore the incidence and clinical presentation of lower gastrointestinal toxicity to immune checkpoint inhibitors among patients with colorectal cancer. While our initial concern was that the presence of malignancy along the colon may predispose to locoregional inflammatory processes, particularly after immune checkpoint inhibition, surprisingly, we found that the incidence of gastrointestinal irAEs in our sample was substantially lower than that found in the literature for other tumor types (14–37%) while potentially being less severe as well[ 10 – 12 ]. Furthermore, our sample demonstrated a delayed onset of toxicity (median of 259 days after ICI) in comparison to the reported time window of 2–3 months. These findings pose interesting questions regarding the mechanism of immune mediated toxicity and the role of the tumor microenvironment as well as the gut microbiome in their development. Colorectal cancer refers to any tumor of the inner lining of the rectum or colon. It is the third most common cancer type comprising 8% of new cancer cases annually and although its incidence and mortality rates have declined in the past decade, it remains among the deadliest types of malignancy when metastatic[ 13 , 14 ]. In CRCs not amenable to resection, systemic treatments are available, the choice of which highly depends on the tumor mutational profile. For instance, current guidelines from the National Comprehensive Cancer Network endorse the use of immune checkpoint inhibitors for the treatment of dMMR/MSI-H CRC, which is predictive of response to ICIs[ 15 – 17 ]. Immunotherapy however comes with the risk of irAEs, of which gastrointestinal toxicities (primarily enterocolitis) are among the more common and severe[ 18 ]. This poses a unique situation where there is regional overlap in cancer location and drug-related organ toxicity, a phenomenon that has yet to be studied adequately in the field of immunotherapy. Previous studies have suggested the existence of tumor-dependent irAE profiles. For instance, one study found that melanoma was associated with a higher incidence of gastrointestinal and cutaneous irAEs and a lower frequency of pulmonary irAEs[ 19 ]. Another study showed that patients with melanoma were more likely to develop cutaneous irAEs while those with non-small cell lung cancer were more likely to develop pulmonary irAEs[ 20 ]. Together, these suggest the potential for locoregional tumor effects that influence the preponderance of inflammatory adverse events, highlighting the complexity of the tumor microenvironment (TME). Though the specific immune phenotype varies greatly between types of cancers depending on the interplay of increased immune activation in response to tumor neoantigens and the activation of immunosuppressive signaling pathways by the tumor to evade the body’s immune surveillance[ 21 ], there is a disruption of immune cell functioning regardless. This conceivably impacts local predisposition to autoimmunity induced by checkpoint inhibitors and is supported by two studies that found that patients who received ipilimumab for active metastatic disease had a lower rate of severe irAEs than those who received it as post-surgical, adjuvant treatment[ 22 , 23 ]. In our study, we found that CRC could potentially mitigate the risk for lower luminal GI irAEs among patients receiving immunotherapy. While these results need to be validated through further studies, it raises an interesting question regarding the impact of tumor burden and location on the incidence of related organ toxicities. Immune checkpoint inhibitors are an effective means of treating cancer by enhancing the human body’s natural immune defenses allowing it to mount an anti-tumor response. Three classes of ICIs have FDA approval with different mechanisms. PD-1/L1 inhibitors block the activity of the programmed death-1/ligand 1 protein which typically suppress cytokine production and immune cell proliferation[ 24 ]. CTLA-4 inhibitors interfere with the activity of the cytotoxic T-lymphocyte antigen 4 protein which serves the dual function of inhibiting T cell costimulation while promoting the activity of regulatory T cells that dampen immune responses[ 25 ]. Finally, the recently approved lymphocyte activation gene 3 inhibitors help reconstitute the immune system after T-cell exhaustion[ 26 ]. These agents induce a potent antitumor immunity which, by the same mechanism, may promote auto-immunity as well. Although the precise mechanism for development of these immune-related adverse events likely differs by the class of ICI used and the system involved, T cells are heavily implicated in this process[ 27 ]. IrAEs can pose a significant obstacle to long-term treatment with ICIs, and extensive research is underway to elucidate the pathophysiology of irAEs and to identify predictive biomarkers for these toxicities[ 27 ]. Of all the risk factors explored, the aforementioned tumor microenvironment has received surprisingly little attention for its role in the pathogenesis of irAEs. Two tumor immunophenotypes are traditionally described based on the degree of immune cell infiltration. Immunologically “hot” tumors are those with a preponderance of tumor-infiltrating lymphocytes (TILs), a strong immune signature, and activation of immune checkpoints by the tumor as a means of circumventing this inflammatory response[ 28 ]. “Cold” tumors, on the other hand are those with sparse inflammatory infiltrate and typically dense, fibrotic stroma[ 29 ]. Some measure of immunosuppression is employed by both phenotypes to allow the cancer to escape immune surveillance, but their responsiveness to immunotherapy differs significantly[ 28 ]. Conceivably, this difference in tumor microenvironment may also impact the risk of irAEs. Microsatellite status is a well-known marker of genomic instability and has been associated with tumor immune phenotype – particularly, MSI-H tumors are considered “hot” and are responsive to ICIs[ 28 , 30 ]. As this remains an understudied phenomenon, future studies are needed to explore the influence of the tumor microenvironment on the risk of irAEs. The gut microbiome in particular closely interacts with the TME and is a promising avenue for future research. The gut microbiome is a complex ecosystem consisting of symbiotic bacteria that has received immense attention in recent years for its influence on physiological functions. Bacterial metabolites such as short-chain fatty acids, bile acids, and amino-acid derivatives have been implicated in various processes including metabolism, inflammation, and immunity[ 31 – 33 ]. With the advent of immunotherapy, there is a growing body of research to show that the gut microbiome is also involved in carcinogenesis and may modulate the effectiveness of cancer treatments, most notably immune checkpoint inhibition[ 34 , 35 ]. It does this by altering the composition of macrophages, natural killer cells, CD4 + and CD8 + T cells in the tumor immune microenvironment and enhancing tumor immunogenicity[ 34 ]. In this way, depending on the specific bacterial composition, the gut microbiome can potentially enhance antitumor immunity and increase cancer susceptibility to immunotherapy[ 36 – 38 ]. While beneficial in terms of cancer outcomes, this remodeling of the tumor immune microenvironment may also impact the risk of immune-related adverse events. One study by Chaput et al. found that melanoma patients colonized with specific species of bacteria had significantly longer progression free survival on ICIs but had a much higher incidence of immune-mediated colitis[ 39 ]. Other studies since have demonstrated the impact of different microbial signatures on the incidence and severity of other irAEs[ 37 , 38 , 40 – 43 ]. This is an especially important area to study in the realm of colorectal cancer as gut dysbiosis is a key feature of the disease[ 44 , 45 ]. It is difficult to ascertain whether the altered microbiome in CRC precedes the cancer or results from it. Nonetheless, it opens up many new avenues in terms of diagnostics and therapeutics[ 46 – 48 ]. Fecal microbiota transplantation in particular has exploded in popularity and is being explored in many clinical trials as a means to augment the efficacy of cancer therapy – especially immune checkpoint inhibition – and to mitigate toxicity to cancer medications[ 49 – 53 ]. It has proven to be highly effective in treating refractory immune-mediated colitis leading to rapid symptom resolution in up to 85.1% of patients and has had promising results as a first-line treatment for this irAE[ 54 , 55 ]. Furthermore, there are currently two trials underway to explore its utility in combination with ICI for treating CRC[ 56 , 57 ]. Its usefulness in CRC and as a means of preventing irAEs remains understudied and could be an untapped vein for future research. This study has several limitations. To start, it was a retrospective study using electronic health records. As such, missing information and subjective interpretation of medical records may affect the accuracy of the data collected. Moreover, other information of interest such as gut microbial composition could not be collected. Given our small sample size, it is difficult to draw robust conclusions. Finally, the lack of a comparison group with different cancer types precludes the possibility of conducting further analysis past the descriptive findings presented. Our study is among the first to explore the clinical manifestation of GI irAEs in patients with colorectal cancer. We found that GI irAEs may occur less frequently with a delayed onset and at a lower severity in patients with CRC compared to those with other cancer types. It is likely that multiple elements such as tumor location, tumor microenvironment, and gut microbiome all factor in to affect the development of GI irAEs in this population. More studies are needed to explore the complex interplay of these features to further elucidate the mechanism of toxicity to checkpoint inhibition. Declarations Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contribution Antonio Pizuorno Machado ( [email protected] ): acquisition of data, data analysis and interpretation, drafting of the manuscript, critical revision of the manuscript for intellectual content Malek Shatila ( [email protected] ): acquisition of data; data analysis; drafting of the manuscript, critical revision of the manuscript for intellectual content Parvir Aujla ( [email protected] ): data analysis and interpretation, drafting of the manuscript, critical revision of the manuscript for intellectual content Ryan Huey ( [email protected] ): data analysis and interpretation, critical revision of the manuscript for intellectual content Yinghong Wang ( [email protected] ): study concept and design; data analysis and interpretation of data; critical revision of the manuscript for intellectual content Anusha S. Thomas ( [email protected] ): study concept and design; data analysis and interpretation of data; critical revision of the manuscript for intellectual content Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. Ethics approval Consent to participate The ethics approval for this study was granted by the institutional review board at The University of Texas MD Anderson Cancer Center (PA18-0472). Patient consent was waived for this study. Conflict of interest The authors declare that they have no conflicts of interest. References Gong, Z. and Y. Wang, Immune Checkpoint Inhibitor-Mediated Diarrhea and Colitis: A Clinical Review. JCO Oncol Pract, 2020. 16 (8): p. 453-461. Prieux-Klotz, C., et al., Immune Checkpoint Inhibitor-Induced Colitis: Diagnosis and Management. Target Oncol, 2017. 12 (3): p. 301-308. 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Yinghong Wang, K.V., Malek Shatila, Shu-En Shen, Mary Herrera, Elizabeth Gonzalez, Xin Shelley Wang, Anusha Thomas, Zhi-Dong Jiang, Herbert L. DuPont, Effect of fecal transplantation on patients’ reported outcome after immune checkpoint inhibitor colitis. Journal of Clinical Oncology, 2023. 41 . Yinghong Wang, K.V., Malek Shatila, Matthew T Campbell, Pavlos Msaouel, and Craig A. Kovitz, First-line treatment of fecal microbiota transplantation for immune-mediated colitis. Journal of Clinical Oncology, 2023. 41 . Chinese Academy of Medical, S. and ChineseAms. FMT Combined With Immune Checkpoint Inhibitor and TKI in the Treatment of CRC Patients With Advanced Stage . 2023 October; Available from: https://classic.clinicaltrials.gov/show/NCT05279677. Center, M.D.A.C. and I. National Cancer. Fecal Microbiota Transplant and Re-introduction of Anti-PD-1 Therapy (Pembrolizumab or Nivolumab) for the Treatment of Metastatic Colorectal Cancer in Anti-PD-1 Non-responders . 2024 December 31; Available from: https://classic.clinicaltrials.gov/show/NCT04729322. Tables Tables 1 to 3 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files colorectalandiraetablesv4final.docx Cite Share Download PDF Status: Published Journal Publication published 01 Oct, 2023 Read the published version in American Journal of Gastroenterology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4248366","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":290563924,"identity":"45df5fb3-7cec-4b6f-abbc-9e7a41f07541","order_by":0,"name":"Antonio Pizuorno Machado","email":"","orcid":"","institution":"The University of Texas Health Science Center","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"Pizuorno","lastName":"Machado","suffix":""},{"id":290563927,"identity":"ea651759-6577-4520-a1f1-4f744654ff11","order_by":1,"name":"Malek Shatila","email":"","orcid":"","institution":"The University of Texas MD Anderson Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Malek","middleName":"","lastName":"Shatila","suffix":""},{"id":290563929,"identity":"33f434cd-81d4-4122-9075-38e4ee79e926","order_by":2,"name":"Parvir Aujla","email":"","orcid":"","institution":"The University of Texas Health Science Center","correspondingAuthor":false,"prefix":"","firstName":"Parvir","middleName":"","lastName":"Aujla","suffix":""},{"id":290563931,"identity":"c463c998-6752-47ff-933c-166063533803","order_by":3,"name":"Ryan Huey","email":"","orcid":"","institution":"The University of Texas MD Anderson Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"","lastName":"Huey","suffix":""},{"id":290563936,"identity":"b102c729-1605-47db-8da4-b10922281cb6","order_by":4,"name":"Yinghong Wang","email":"","orcid":"","institution":"The University of Texas MD Anderson Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Yinghong","middleName":"","lastName":"Wang","suffix":""},{"id":290563938,"identity":"957bad46-b759-42c1-8457-1de42b27b5d2","order_by":5,"name":"Anusha Thomas","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIie3OsUvDQBTH8VcC6ZI06wvR5F9oECoSSP6VOw6SpZlcCh2a6Zyka/pnSOFwrBzEJSVrXKSTiwh27CCY2vmk2UTuO7ztw+8B6HR/M/N0hwUggHGOME5kZG36Eh/JmcRZNtVuP40T032n7eEx8q+XstrB7DUuFARbNgxXglHu5eub+zq7umjTbAz1LVMRaA3Ts4VBTC8XaHNJS7QmOOCEqUTQyCNZdI9thfvF5aJ06t/JeMOORA442sLrVgjC9IfEKhK2bOKuxDPlVr6OLnkWlpimSGpCVMRvnt5wL+ZJcLd9ePngUYCOrPBzRhIVUdRN0KKnAei7otPpdP+3b7YzUQ1b8Y5OAAAAAElFTkSuQmCC","orcid":"","institution":"The University of Texas MD Anderson Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Anusha","middleName":"","lastName":"Thomas","suffix":""}],"badges":[],"createdAt":"2024-04-10 16:02:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4248366/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4248366/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.14309/01.ajg.0000950364.42958.76","type":"published","date":"2023-10-01T18:45:33+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55004032,"identity":"34daf36c-921a-4098-9df7-0a7b9a073b41","added_by":"auto","created_at":"2024-04-19 18:44:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":55944,"visible":true,"origin":"","legend":"\u003cp\u003ePatient Selection diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4248366/v1/69907a36a0de4edcedc24142.png"},{"id":55007754,"identity":"1746f4fc-8f57-4341-b216-fc5c3ed331b2","added_by":"auto","created_at":"2024-04-19 19:00:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":368379,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4248366/v1/be31cc07-db79-460b-8135-8c31b68d3222.pdf"},{"id":55004060,"identity":"8367810d-7839-4c50-bc92-163683ae61b1","added_by":"auto","created_at":"2024-04-19 18:44:50","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":24077,"visible":true,"origin":"","legend":"","description":"","filename":"colorectalandiraetablesv4final.docx","url":"https://assets-eu.researchsquare.com/files/rs-4248366/v1/71793e288e26bff12f42e282.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Immune checkpoint inhibitor-associated gastrointestinal adverse events in patients with colorectal cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmune checkpoint inhibitors (ICIs) are a potent and increasingly important treatment option for various malignancies. To date, more than eight ICI agents have been approved. While conferring an appreciable survival benefit, these agents also predispose to unique immune-related gastrointestinal adverse events (irAEs), with diarrhea and colitis amongst the most common.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Immune-mediated colitis (IMC) has been reported in up to 40% of patients treated with ICIs. It varies widely in severity[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and can be a cause for discontinuation of ICI therapy[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Failure in early recognition and delayed or suboptimal treatment early in the disease course can lead to an increased risk of complications such as bowel perforation[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e The use of ICIs to treat MSI-H colon cancer is a relatively recent advancement. One clinical trial showed pembrolizumab can lead to significantly longer progression-free survival than chemotherapy when received as first-line therapy for microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR)\u0026ndash;metastatic colorectal cancer, with fewer treatment-related adverse events[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Several studies have shown activity and clinical benefit for ICIs in colorectal cancer[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, much remains to be learned about irAE for this patient population. Given their novelty, our knowledge of their potential irAEs in this setting is still limited. Ostensibly, the presence of malignancy in the bowel may uniquely impact the risk and severity of gastrointestinal irAEs specifically.\u003c/p\u003e \u003cp\u003eThere have been limited large-scale studies investigating the safety of ICIs in patients with colorectal cancer in terms of irAE. In this retrospective study, we explored the incidence and clinical manifestations of immune-mediated colitis among patients with colorectal cancer.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003e This retrospective chart review is a descriptive, single-center study that included adult patients who were diagnosed with colorectal cancer and treated with ICI at a tertiary cancer center between 6/1/2014 and 12/31/2022. This study was approved by the institutional review board with a waiver of patients\u0026rsquo; informed consent. We identified adult cancer patients 18 years or older who (1) were treated with ICIs for colorectal cancer, and (2) had a diagnosis of immune-mediated colitis at least 3 months after the last ICI dose. Patients with pre-existing inflammatory bowel disease (IBD), microscopic colitis, or other autoimmune gastrointestinal disorders were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eClinical data\u003c/h2\u003e \u003cp\u003eDemographic and cancer-related information such as age, gender, primary cancer type, stage, cancer treatments received and doses, and Charlson Comorbidity Index score were collected. Also collected were data related to the onset of colitis, such as date, cycles of ICI before colitis, type of ICI, and peak Common Terminology Criteria for Adverse Events (CTCAE) grades for colitis and diarrhea. Diagnosis of colitis was based on the clinical presentation and endoscopic and histologic features after the exclusion of other etiologies. Information about the treatment for colitis such as steroids, infliximab, and vedolizumab, including doses and start and end dates, was obtained as well. Colonoscopy/sigmoidoscopy and pathology findings at the time of colitis diagnosis were reported if available.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe statistical analyses performed were descriptive in nature. The distributions of continuous variables were summarized by medians and interquartile ranges. The distributions of categorical variables were summarized by frequencies and percentages. These were calculated using SPSS 26.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient population, characteristics and oncologic history\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe identified 474 patients with diagnosis of CRC that had exposure to ICI between June 2014 and December 2022. Of there, only 18 patients met our inclusion criteria (see patient selection diagram). Included patients had a median age of 69.5 years with 11 patients (61.1%) being female and 16 patients (88.8%) being white (\u003cstrong\u003eTable 1\u003c/strong\u003e). As for oncological history, 18 patients (100%) were diagnosed with colorectal cancer, followed by overlapped melanoma in 2 patients (11.1%), genitourinary cancer in 1 patient (5.5%). The majority of the patients (n=13, 72.2%), had stage IV cancer. 12 patients (66.6%) had an MSI-H CRC. With regard to class of ICI that patients received, 9 (50%), 8 (44.4%) and 1 (5.5%) patients received a combination of PD-1/L1 and CTLA-4 combination therapy, PD-1/L1 inhibitor monotherapy and CTLA-4 monotherapy respectively. \u0026nbsp;Patients underwent a median of 6 cycles of ICI. After the colitis event, 5 patients (27.7%) continued with ICI and 2 patients (5.8%) continued with other forms of cancer therapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCharacteristics of colitis\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe predominant symptom was diarrhea in all 18 patients (100%), and abdominal pain in 18 patients (100%) (\u003cstrong\u003eTable 2\u003c/strong\u003e); colitis presented in a median of 259 days after initiating ICI (\u003cstrong\u003eTable 1\u003c/strong\u003e). The median fecal calprotectin before treatment was 641mcg/g. Median peak CTCAE of colitis was 1 and for diarrhea was 2 (\u003cstrong\u003eTable 2\u003c/strong\u003e). The majority of the patients had grade 1 colitis in 10 patients (55.5%). Hospitalization was required for 4 patients (22.2%). As for the treatment of colitis, steroids were used in the entire cohort, and in conjunction with vedolizumab (1 patient, 5.5%) or infliximab alone (3 patients, 16.6%). Fecal microbiota transplant was performed in 1 patient (5.5%) (\u003cstrong\u003eTable 3\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEndoscopic and histology related characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the time of colitis diagnosis only 5 patients underwent an endoscopic procedure. Non-ulcer inflammation was found in 2 patients (40%), same frequency was seen ulcerative inflammation (2 patients, 40%). On histology, the majority had active inflammation (4 patients, 80%) (\u003cstrong\u003eTable 3\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study, to our knowledge is the first to explore the incidence and clinical presentation of lower gastrointestinal toxicity to immune checkpoint inhibitors among patients with colorectal cancer. While our initial concern was that the presence of malignancy along the colon may predispose to locoregional inflammatory processes, particularly after immune checkpoint inhibition, surprisingly, we found that the incidence of gastrointestinal irAEs in our sample was substantially lower than that found in the literature for other tumor types (14\u0026ndash;37%) while potentially being less severe as well[\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Furthermore, our sample demonstrated a delayed onset of toxicity (median of 259 days after ICI) in comparison to the reported time window of 2\u0026ndash;3 months. These findings pose interesting questions regarding the mechanism of immune mediated toxicity and the role of the tumor microenvironment as well as the gut microbiome in their development.\u003c/p\u003e \u003cp\u003eColorectal cancer refers to any tumor of the inner lining of the rectum or colon. It is the third most common cancer type comprising 8% of new cancer cases annually and although its incidence and mortality rates have declined in the past decade, it remains among the deadliest types of malignancy when metastatic[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In CRCs not amenable to resection, systemic treatments are available, the choice of which highly depends on the tumor mutational profile. For instance, current guidelines from the National Comprehensive Cancer Network endorse the use of immune checkpoint inhibitors for the treatment of dMMR/MSI-H CRC, which is predictive of response to ICIs[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Immunotherapy however comes with the risk of irAEs, of which gastrointestinal toxicities (primarily enterocolitis) are among the more common and severe[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This poses a unique situation where there is regional overlap in cancer location and drug-related organ toxicity, a phenomenon that has yet to be studied adequately in the field of immunotherapy. Previous studies have suggested the existence of tumor-dependent irAE profiles. For instance, one study found that melanoma was associated with a higher incidence of gastrointestinal and cutaneous irAEs and a lower frequency of pulmonary irAEs[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Another study showed that patients with melanoma were more likely to develop cutaneous irAEs while those with non-small cell lung cancer were more likely to develop pulmonary irAEs[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Together, these suggest the potential for locoregional tumor effects that influence the preponderance of inflammatory adverse events, highlighting the complexity of the tumor microenvironment (TME). Though the specific immune phenotype varies greatly between types of cancers depending on the interplay of increased immune activation in response to tumor neoantigens and the activation of immunosuppressive signaling pathways by the tumor to evade the body\u0026rsquo;s immune surveillance[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], there is a disruption of immune cell functioning regardless. This conceivably impacts local predisposition to autoimmunity induced by checkpoint inhibitors and is supported by two studies that found that patients who received ipilimumab for active metastatic disease had a lower rate of severe irAEs than those who received it as post-surgical, adjuvant treatment[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In our study, we found that CRC could potentially mitigate the risk for lower luminal GI irAEs among patients receiving immunotherapy. While these results need to be validated through further studies, it raises an interesting question regarding the impact of tumor burden and location on the incidence of related organ toxicities.\u003c/p\u003e \u003cp\u003eImmune checkpoint inhibitors are an effective means of treating cancer by enhancing the human body\u0026rsquo;s natural immune defenses allowing it to mount an anti-tumor response. Three classes of ICIs have FDA approval with different mechanisms. PD-1/L1 inhibitors block the activity of the programmed death-1/ligand 1 protein which typically suppress cytokine production and immune cell proliferation[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. CTLA-4 inhibitors interfere with the activity of the cytotoxic T-lymphocyte antigen 4 protein which serves the dual function of inhibiting T cell costimulation while promoting the activity of regulatory T cells that dampen immune responses[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Finally, the recently approved lymphocyte activation gene 3 inhibitors help reconstitute the immune system after T-cell exhaustion[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. These agents induce a potent antitumor immunity which, by the same mechanism, may promote auto-immunity as well. Although the precise mechanism for development of these immune-related adverse events likely differs by the class of ICI used and the system involved, T cells are heavily implicated in this process[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. IrAEs can pose a significant obstacle to long-term treatment with ICIs, and extensive research is underway to elucidate the pathophysiology of irAEs and to identify predictive biomarkers for these toxicities[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Of all the risk factors explored, the aforementioned tumor microenvironment has received surprisingly little attention for its role in the pathogenesis of irAEs. Two tumor immunophenotypes are traditionally described based on the degree of immune cell infiltration. Immunologically \u0026ldquo;hot\u0026rdquo; tumors are those with a preponderance of tumor-infiltrating lymphocytes (TILs), a strong immune signature, and activation of immune checkpoints by the tumor as a means of circumventing this inflammatory response[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. \u0026ldquo;Cold\u0026rdquo; tumors, on the other hand are those with sparse inflammatory infiltrate and typically dense, fibrotic stroma[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Some measure of immunosuppression is employed by both phenotypes to allow the cancer to escape immune surveillance, but their responsiveness to immunotherapy differs significantly[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Conceivably, this difference in tumor microenvironment may also impact the risk of irAEs. Microsatellite status is a well-known marker of genomic instability and has been associated with tumor immune phenotype \u0026ndash; particularly, MSI-H tumors are considered \u0026ldquo;hot\u0026rdquo; and are responsive to ICIs[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. As this remains an understudied phenomenon, future studies are needed to explore the influence of the tumor microenvironment on the risk of irAEs. The gut microbiome in particular closely interacts with the TME and is a promising avenue for future research.\u003c/p\u003e \u003cp\u003eThe gut microbiome is a complex ecosystem consisting of symbiotic bacteria that has received immense attention in recent years for its influence on physiological functions. Bacterial metabolites such as short-chain fatty acids, bile acids, and amino-acid derivatives have been implicated in various processes including metabolism, inflammation, and immunity[\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. With the advent of immunotherapy, there is a growing body of research to show that the gut microbiome is also involved in carcinogenesis and may modulate the effectiveness of cancer treatments, most notably immune checkpoint inhibition[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. It does this by altering the composition of macrophages, natural killer cells, CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e T cells in the tumor immune microenvironment and enhancing tumor immunogenicity[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In this way, depending on the specific bacterial composition, the gut microbiome can potentially enhance antitumor immunity and increase cancer susceptibility to immunotherapy[\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. While beneficial in terms of cancer outcomes, this remodeling of the tumor immune microenvironment may also impact the risk of immune-related adverse events. One study by Chaput et al. found that melanoma patients colonized with specific species of bacteria had significantly longer progression free survival on ICIs but had a much higher incidence of immune-mediated colitis[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Other studies since have demonstrated the impact of different microbial signatures on the incidence and severity of other irAEs[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan additionalcitationids=\"CR41 CR42\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. This is an especially important area to study in the realm of colorectal cancer as gut dysbiosis is a key feature of the disease[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. It is difficult to ascertain whether the altered microbiome in CRC precedes the cancer or results from it. Nonetheless, it opens up many new avenues in terms of diagnostics and therapeutics[\u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Fecal microbiota transplantation in particular has exploded in popularity and is being explored in many clinical trials as a means to augment the efficacy of cancer therapy \u0026ndash; especially immune checkpoint inhibition \u0026ndash; and to mitigate toxicity to cancer medications[\u003cspan additionalcitationids=\"CR50 CR51 CR52\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. It has proven to be highly effective in treating refractory immune-mediated colitis leading to rapid symptom resolution in up to 85.1% of patients and has had promising results as a first-line treatment for this irAE[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e, \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. Furthermore, there are currently two trials underway to explore its utility in combination with ICI for treating CRC[\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Its usefulness in CRC and as a means of preventing irAEs remains understudied and could be an untapped vein for future research.\u003c/p\u003e \u003cp\u003eThis study has several limitations. To start, it was a retrospective study using electronic health records. As such, missing information and subjective interpretation of medical records may affect the accuracy of the data collected. Moreover, other information of interest such as gut microbial composition could not be collected. Given our small sample size, it is difficult to draw robust conclusions. Finally, the lack of a comparison group with different cancer types precludes the possibility of conducting further analysis past the descriptive findings presented.\u003c/p\u003e \u003cp\u003eOur study is among the first to explore the clinical manifestation of GI irAEs in patients with colorectal cancer. We found that GI irAEs may occur less frequently with a delayed onset and at a lower severity in patients with CRC compared to those with other cancer types. It is likely that multiple elements such as tumor location, tumor microenvironment, and gut microbiome all factor in to affect the development of GI irAEs in this population. More studies are needed to explore the complex interplay of these features to further elucidate the mechanism of toxicity to checkpoint inhibition.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAntonio Pizuorno Machado\u0026nbsp;([email protected]): acquisition of data, data analysis and interpretation, drafting of the manuscript, critical revision of the manuscript for intellectual content \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMalek Shatila ([email protected]): acquisition of data; data analysis; drafting of the manuscript, critical revision of the manuscript for intellectual content \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParvir Aujla ([email protected]): data analysis and interpretation,\u0026nbsp;drafting of the manuscript,\u0026nbsp;critical revision of the manuscript\u0026nbsp;for intellectual content\u003c/p\u003e\n\u003cp\u003eRyan Huey ([email protected]): data analysis and interpretation, critical revision of the manuscript for intellectual content \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYinghong Wang\u0026nbsp;([email protected]): study concept and design; data analysis and interpretation of data; critical revision of the manuscript for intellectual content \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnusha S. Thomas\u0026nbsp;([email protected]): study concept and design; data analysis and interpretation of data; critical revision of the manuscript for intellectual content \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;to\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ethics approval for this study was granted by the institutional review board at The University of Texas MD Anderson Cancer Center (PA18-0472). Patient consent was waived for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGong, Z. and Y. 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National Cancer. \u003cem\u003eFecal Microbiota Transplantation in Treating Immune-Checkpoint Inhibitor Induced-Diarrhea or Colitis in Genitourinary Cancer Patients\u003c/em\u003e. 2025 April 30; Available from: https://classic.clinicaltrials.gov/show/NCT04038619.\u003c/li\u003e\n\u003cli\u003eFondazione Policlinico Universitario Agostino Gemelli, I. \u003cem\u003eFecal Microbiota Transplantation to Improve Efficacy of Immune Checkpoint Inhibitors in Renal Cell Carcinoma\u003c/em\u003e. 2024 February 19; Available from: https://classic.clinicaltrials.gov/show/NCT04758507.\u003c/li\u003e\n\u003cli\u003eMichael, S. and Z. University of. \u003cem\u003eFecal Microbiota Transplantation in Patients With Malignancies Not Responding to Immune Checkpoint Inhibitor Therapy\u003c/em\u003e. 2025 January 31; Available from: https://classic.clinicaltrials.gov/show/NCT05273255.\u003c/li\u003e\n\u003cli\u003eThe Netherlands Cancer, I. \u003cem\u003eFMT to Convert Response to Immunotherapy\u003c/em\u003e. 2024 April; Available from: https://classic.clinicaltrials.gov/show/NCT05251389.\u003c/li\u003e\n\u003cli\u003eYinghong Wang, K.V., Malek Shatila, Shu-En Shen, Mary Herrera, Elizabeth Gonzalez, Xin Shelley Wang, Anusha Thomas, Zhi-Dong Jiang, Herbert L. DuPont, \u003cem\u003eEffect of fecal transplantation on patients\u0026rsquo; reported outcome after immune checkpoint inhibitor colitis.\u003c/em\u003e Journal of Clinical Oncology, 2023. \u003cstrong\u003e41\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eYinghong Wang, K.V., Malek Shatila, Matthew T Campbell, Pavlos Msaouel, and Craig A. Kovitz, \u003cem\u003eFirst-line treatment of fecal microbiota transplantation for immune-mediated colitis.\u003c/em\u003e Journal of Clinical Oncology, 2023. \u003cstrong\u003e41\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eChinese Academy of Medical, S. and ChineseAms. \u003cem\u003eFMT Combined With Immune Checkpoint Inhibitor and TKI in the Treatment of CRC Patients With Advanced Stage\u003c/em\u003e. 2023 October; Available from: https://classic.clinicaltrials.gov/show/NCT05279677.\u003c/li\u003e\n\u003cli\u003eCenter, M.D.A.C. and I. National Cancer. \u003cem\u003eFecal Microbiota Transplant and Re-introduction of Anti-PD-1 Therapy (Pembrolizumab or Nivolumab) for the Treatment of Metastatic Colorectal Cancer in Anti-PD-1 Non-responders\u003c/em\u003e. 2024 December 31; Available from: https://classic.clinicaltrials.gov/show/NCT04729322.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Immune checkpoint inhibitors, Colorectal cancer, Immune related adverse event, Colitis ","lastPublishedDoi":"10.21203/rs.3.rs-4248366/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4248366/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e Immune checkpoint inhibitors (ICI) are currently employed for the management of microsatellite instability-high (MSI-H) tumors with success. While immune checkpoint inhibitor related colitis is a very frequent and a devastating immune related adverse event (irAE) with the use of these agents, the incidence and characteristics of this inflammatory toxicity in patients with MSI-H colorectal cancers has not been examined. We aimed to describe the characteristics and clinical profile of patients diagnosed with luminal gastrointestinal irAE in patients treated with ICI for colorectal cancer in a tertiary cancer care center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis is a retrospective analysis that included adult cancer patients diagnosed with colorectal cancer that received ICI between 6/1/2014 and 12/31/2022. We report data on those that developed colitis as an irAE up to 3 months after the last dose of ICI confirmed by laboratory and/or imaging report. We included patients’ demographic characteristics, oncologic profile and outcomes as well as clinical course, endoscopic features as well as treatment and outcomes in terms of luminal gastrointestinal irAEs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Out of 474 patients with colorectal cancer on ICI in our study period, only 18 developed a gastrointestinal irAE with an incidence of 3.8%. Patients were primarily Caucasian (88.8%) males (61.1%) with a median age of 69.5 years. The majority of these patients received combination therapy with anti-PD-1/L1 and CTLA-4 (50%). 66.6 % received ICI for MSI-H colorectal cancer. 11.1% of our sample were noted to have a second cancer-melanoma. The majority of patients had grade 1-2 colitis (61.2%) and grade 1-2 diarrhea (88.8%). Only 5 patients underwent endoscopic evaluation of whom, 2 had ulcerative inflammation necessitating use of selective immunosuppressive therapy with biologics. 61.1% had to withhold cancer treatment due toxicity. With regards to other gastrointestinal irAEs among this population, 41.4% and 5.8% were noted to have liver and pancreas toxicity respectively, with a median CTCAE grade of severity 2. The majority of our cohort received steroids as therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eLuminal\u003cstrong\u003e \u003c/strong\u003egastrointestinal irAEs seem to occur less frequently and at a lower severity among patients with MSI-H colorectal cancer after checkpoint inhibitors exposure compared to the overall incidence of the same among other cancers reported in literature. Larger prospective studies are necessary to determine the role of tumor biology and the gut microbiome in the disease profile and severity of immune related adverse events of the GI organ system.\u003c/p\u003e","manuscriptTitle":"Immune checkpoint inhibitor-associated gastrointestinal adverse events in patients with colorectal cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-19 18:44:37","doi":"10.21203/rs.3.rs-4248366/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"30d804b6-8444-4003-89e0-191f1321e955","owner":[],"postedDate":"April 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-04-19T18:45:33+00:00","versionOfRecord":{"articleIdentity":"rs-4248366","link":"https://doi.org/10.14309/01.ajg.0000950364.42958.76","journal":{"identity":"american-journal-of-gastroenterology","isVorOnly":true,"title":"American Journal of Gastroenterology"},"publishedOn":"2023-10-01 18:45:33","publishedOnDateReadable":"October 1st, 2023"},"versionCreatedAt":"2024-04-19 18:44:37","video":"","vorDoi":"10.14309/01.ajg.0000950364.42958.76","vorDoiUrl":"https://doi.org/10.14309/01.ajg.0000950364.42958.76","workflowStages":[]},"version":"v1","identity":"rs-4248366","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4248366","identity":"rs-4248366","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}