For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
5
views
64
references
 Top references
cited by
22
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      204
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Pathology of immune-mediated tissue lesions following treatment with immune checkpoint inhibitors

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Immune check point inhibitor (CPI) therapy has revolutionized treatment paradigms for several cancers, but at the cost of triggering a diverse spectrum of immune-mediated injury to non-cancer tissues. The complex biology of these toxicities remains incompletely understood, partly because tissue acquisition from affected areas can be challenging to retrieve, thus hindering development of targeted therapy. Here, we review the literature describing pathology of immune-mediated tissue lesions including gastrointestinal, skin, rheumatic, pulmonary, cardiac, renal and hepatic lesions and highlight key immunological insights.

          Related collections

          Most cited references64

          • Record: found
          • Abstract: found
          • Article: not found

          Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.

          Kimberly E Beck, Joseph A. Blansfield, Khoi Tran … (2006)
          Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is an inhibitory receptor on T cells. Knocking out CTLA4 in mice causes lethal lymphoproliferation, and polymorphisms in human CTLA4 are associated with autoimmune disease. Trials of the anti-CTLA4 antibody ipilimumab (MDX-010) have resulted in durable cancer regression and immune-mediated toxicities. A report on the diagnosis, pathology, treatment, clinical outcome, and significance of the immune-mediated enterocolitis seen with ipilimumab is presented. We treated 198 patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) with ipilimumab. The overall objective tumor response rate was 14%. We observed several immune mediated toxicities including dermatitis, enterocolitis, hypophysitis, uveitis, hepatitis, and nephritis. Enterocolitis, defined by grade 3/4 clinical presentation and/or biopsy documentation, was the most common major toxicity (21% of patients). It presented with diarrhea, and biopsies showed both neutrophilic and lymphocytic inflammation. Most patients who developed enterocolitis responded to high-dose systemic corticosteroids. There was no evidence that steroid administration affected tumor responses. Five patients developed perforation or required colectomy. Four other patients with steroid-refractory enterocolitis appeared to respond promptly to tumor necrosis factor alpha blockade with infliximab. Objective tumor response rates in patients with enterocolitis were 36% for MM and 35% for RCC, compared with 11% and 2% in patients without enterocolitis, respectively (P = .0065 for MM and P = .0016 for RCC). CTLA4 seems to be a significant component of tolerance to tumor and in protection against immune mediated enterocolitis and these phenomena are significantly associated in cancer patients.
          Article 0 comments Cited 209 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma

            Ahmad Tarhini, Haris Zahoor, Yan Lin … (2015)
            Background We evaluated candidate circulating serum cytokines, chemokines and growth factors in patients with locally/regionally advanced melanoma receiving neoadjuvant ipilimumab with toxicity and clinical outcome. Methods Patients were treated with ipilimumab (10 mg/kg IV every 3 weeks, 2 doses) before and after surgery. xMAP multiplex serum testing for 36 functionally selected cytokines and chemokines was performed at baseline and at six weeks (following ipilimumab). Based on our prior data, the association of IL-17 and immune related colitis was tested. Serum cytokines were divided into functional groups (Th1, Th2, Regulatory, Proinflammatory) and were assessed at baseline and week 6 using sparse-group Lasso modeling to assess the association of various cytokine groups with progression free survival (PFS). The linear combination of the cytokines/chemokines in this model was then used as a risk score and a Kaplan-Meier curve was generated to examine the association of the dichotomized score and PFS. Results Thirty-five patients were enrolled whose staging was: IIIB (3; N2b), IIIC (30; N2c, N3), IV (2). Median follow-up was 18 months. Among 33 evaluable patients, median PFS was 11 months (95 % CI = 6.2–19.2). IL-17 was found to correlate significantly with the incidence of grade 3 diarrhea/colitis when measured at baseline (p = 0.02) with a trend towards significance at 6 weeks (p = 0.06). In the modeling analysis, at baseline, the linear combination of 2 regulatory cytokines [TGF- β1 (ρ = 0.19) and IL-10 (ρ = -0.34)] was significantly associated with PFS (HR 2.66; p = 0.035). No significant correlations with clinical outcomes were found in examining the week 6 cytokines. Conclusions Baseline IL-17 level was significantly associated with the later development of severe diarrhea/colitis while the combination of baseline TGF- β1 and IL-10 levels were associated with therapeutic clinical outcome after neoadjuvant ipilimumab. These findings warrant further investigation and validation. Trial registration ClinicalTrials.gov Identifier NCT00972933.
            Article 0 comments Cited 182 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              The Price of Tumor Control: An Analysis of Rare Side Effects of Anti-CTLA-4 Therapy in Metastatic Melanoma from the Ipilimumab Network

              Caroline Voskens, Simone Goldinger, Carmen Loquai … (2013)
              Background Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
              Article 0 comments Cited 154 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-ta): Rheumatology (Oxford)
                Journal ID (iso-abbrev): Rheumatology (Oxford)
                Journal ID (publisher-id): brheum
                Title: Rheumatology (Oxford, England)
                Publisher: Oxford University Press
                ISSN (Print): 1462-0324
                ISSN (Electronic): 1462-0332
                Publication date (Print): December 2019
                Publication date (Electronic): 09 December 2019
                Publication date PMC-release: 09 December 2019
                Volume: 58
                Issue: Suppl 7 , The rheumatic side-effects of immuno-oncology treatment
                Pages: vii17-vii28
                Affiliations
                [1 ] Division of Digestive Diseases, Faculty of Medicine, Imperial College London , UK
                [2 ] Gastroenterology Unit, Royal Marsden Hospital , London, UK
                [3 ] Centre for Inflammation Biology and Cancer Immunology, Centre for Rheumatic Diseases, King’s College London
                Author notes

                Hajir Ibraheim and Esperanza Perucha contributed equally to this paper.

                Correspondence to: Nick Powell, Division of Digestive Diseases, Imperial College London, 10th Floor QEQM building, St Mary's Hospital, Praed Street, London W2 1NY, UK. E-mail: npowell@ 123456ic.ac.uk
                Author information
                http://orcid.org/0000-0002-0563-2547
                Article
                Publisher ID: kez465
                DOI: 10.1093/rheumatology/kez465
                PMC ID: 6900915
                PubMed ID: 31816081
                SO-VID: 71f66ad2-b3cb-432b-b17e-0d7f20d8cc61
                Copyright © © The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Date received : 21 May 2019
                Date revision received : 5 September 2019
                Page count
                Pages: 12
                Funding
                Funded by: BMS 10.13039/100002491
                Categories
                Subject: Supplement Articles

                ScienceOpen disciplines: Rheumatology
                Keywords: irae pathology,cpi enterocolitis,cpi skin toxicity,cpi renal injury,cpi rheumatic toxicity,cpi hepatitis,cpi pulmonary toxicity,cpi cardiac toxicity
                Data availability:
                ScienceOpen disciplines: Rheumatology
                Keywords: irae pathology, cpi enterocolitis, cpi skin toxicity, cpi renal injury, cpi rheumatic toxicity, cpi hepatitis, cpi pulmonary toxicity, cpi cardiac toxicity

                Comments

                Comment on this article

                scite_

                Similar content204

                See all similar

                Cited by22

                See all cited by

                Most referenced authors1,213

                See all reference authors