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Mark W. D. Sweep

Bio: Mark W. D. Sweep is an academic researcher from Radboud University Nijmegen. The author has contributed to research in topics: Colitis & Immune system. The author has co-authored 1 publications.

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TL;DR: In this paper, the authors discuss important pathways that are altered in IMC in mouse models and in human colon biopsy samples and propose to focus on T-cell subsets that interact with bacteria after inducing epithelial damage.
Abstract: Immune checkpoint inhibitors (ICIs) have provided tremendous clinical benefit in several cancer types. However, systemic activation of the immune system also leads to several immune-related adverse events. Of these, ICI-mediated colitis (IMC) occurs frequently and is the one with the highest absolute fatality. To improve current treatment strategies, it is important to understand the cellular mechanisms that induce this form of colitis. In this review, we discuss important pathways that are altered in IMC in mouse models and in human colon biopsy samples. This reveals a complex interplay between several types of immune cells and the gut microbiome. In addition to a mechanistic understanding, patients at risk should be identifiable before ICI therapy. Here we propose to focus on T-cell subsets that interact with bacteria after inducing epithelial damage. Especially, intestinal resident immune cells are of interest. This may lead to a better understanding of IMC and provides opportunities for prevention and management.

10 citations


Cited by
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TL;DR: In this article , the authors sought to identify the answers to four questions: 1. what type of cancer has more severe hypersensitivity reactions to Nivolumab, 2. what is the time frame for developing these severe reactions to nivolumaab, 3. whether it is best to continue or stop the treatment after a severe hypersensitive reaction to NIVolumaba, and 4. what severe hypersensation reactions are the most frequent reported along Nivilumab treatment.
Abstract: Immune-checkpoint inhibitors (ICIs) are the most effective treatments nowadays. Nivolumab was the second ICI used for treating solid tumors with amazing results. Patients treated with Nivolumab may react differently to this treatment. Some people tolerate this treatment very well without experiencing any adverse reactions, whilst some may have mild symptoms and a part of them can present severe reactions. In our research, we sought to identify the answers to four questions: 1. what type of cancer has more severe hypersensitivity reactions to Nivolumab, 2. what is the time frame for developing these severe reactions to Nivolumab, 3. whether it is best to continue or stop the treatment after a severe hypersensitivity reaction to Nivolumab and 4. what severe hypersensitivity reactions are the most frequent reported along Nivolumab treatment. This review also highlights another problem with regard to the usage of concomitant and prior medications or other methods of treatment (e.g., radiation therapy), which can also lead to severe reactions. Treatment with Nivolumab is very well tolerated, but patients should also be warned of the possibility of severe hypersensitivity reactions for which they should urgently see a doctor for a personalized evaluation. There are some options for individuals with severe hypersensitivity reactions, for eg. switching the medication or applying a desensitization protocol.

3 citations

Journal ArticleDOI
TL;DR: An improved understanding of the mechanistic basis of cutaneous irAEs will allow clinicians to develop and use blood‐based biomarkers that could help ultimately predict onset and/or severity of theseIrAEs, and to implement rational mechanistic‐based treatment strategies that are targeted to the irAES while potentially avoiding reducing the anti‐tumour effect of ICIs.
Abstract: The discovery of immune checkpoint inhibition (ICI) sparked a revolution in the era of targeted anticancer therapy. However, although monoclonal antibodies targeting the cytotoxic T‐lymphocyte antigen‐4 and programmed death‐1 axes have improved survival in patients with advanced cancers, these immunotherapies are associated with a wide spectrum of dermatological immune‐related adverse events (irAEs), ranging from mild to life‐threatening. Several publications have addressed the clinical and histopathological classification of these skin‐directed irAEs, their impact on anti‐tumour immunity and survival, and the critical role of supportive oncological dermatology in their management. In this paper, we review the current understanding of the mechanistic drivers of immune‐related skin toxicities with a focus on inflammatory, immunobullous and melanocyte/pigment‐related reactions. We detail the specific immune‐based mechanisms that may underlie different cutaneous reactions. We also discuss potential mechanisms as they relate to extracutaneous irAEs and the lessons learned from these, the potential overlap with cutaneous irAEs, techniques to study differences in immune‐related vs. de novo skin reactions, and how treatment of these AEs impacts cancer treatment, patient quality of life and overall survival. An improved understanding of the mechanistic basis of cutaneous irAEs will allow clinicians to develop and use blood‐based biomarkers that could help ultimately predict onset and/or severity of these irAEs, and to implement rational mechanistic‐based treatment strategies that are targeted to the irAEs while potentially avoiding reducing the anti‐tumour effect of ICIs.

2 citations

Journal ArticleDOI
TL;DR: Imaging with [18F]AlF-NOTA-KCNA3P demonstrated that adjuvant metformin significantly improved anti-PD1 efficacy and led to a robust anti-tumour immunological memory response in a syngeneic colon cancer model through changes in tumour infiltrating effector memory T-cells.
Abstract: The low response rates associated with immune checkpoint inhibitor (ICI) use has led to a surge in research investigating adjuvant combination strategies in an attempt to enhance efficacy. Repurposing existing drugs as adjuvants accelerates the pace of cancer immune therapy research; however, many combinations exacerbate the immunogenic response elicited by ICIs and can lead to adverse immune-related events. Metformin, a widely used type 2 diabetes drug is an ideal candidate to repurpose as it has a good safety profile and studies suggest that metformin can modulate the tumour microenvironment, promoting a favourable environment for T cell activation but has no direct action on T cell activation on its own. In the current study we used PET imaging with [18F]AlF-NOTA-KCNA3P, a radiopharmaceutical specifically targeting KV1.3 the potassium channel over-expressed on active effector memory T-cells, to determine whether combining PD1 with metformin leads to an enhanced immunological memory response in a preclinical colorectal cancer model. Flow cytometry was used to assess which immune cell populations infiltrate the tumours in response to the treatment combination. Imaging with [18F]AlF-NOTA-KCNA3P demonstrated that adjuvant metformin significantly improved anti-PD1 efficacy and led to a robust anti-tumour immunological memory response in a syngeneic colon cancer model through changes in tumour infiltrating effector memory T-cells.

1 citations

Journal ArticleDOI
TL;DR: In this article , a case with grade 3 diarrhea and grade 2 colitis following systemic chemotherapy, successfully treated with prednisolone, was reported, where the patient was treated with lenvatinib for 1 year and 4 months, achieving a complete response according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria.
Abstract: Systemic chemotherapy has shown a significant survival benefit in patients with hepatocellular carcinoma (HCC). However, it is associated with various immune-related adverse events (irAEs). We report a case with grade 3 diarrhea and grade 2 colitis following systemic chemotherapy, successfully treated with prednisolone. An 89-year-old man was incidentally detected with a 140-mm hypervascular intrahepatic nodule on contrast-enhanced computed tomography (CECT). Washout of the contrast medium was also detected, and protein induced by vitamin K deficiency or antagonists-II (PIVKA-II) was elevated. Since the Albumin-Bilirubin (ALBI) grade was 2a without any distant metastasis, transarterial chemoembolization (TACE) was performed to treat the HCC, but several intrahepatic nodules were seen in both lobes. Therefore, the patient was treated with lenvatinib for 1 year and 4 months. A complete response according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was achieved in 2 months; however, multiple hypervascular nodules were detected again. Since the ALBI grade was 1, a second round of chemotherapy with atezolizumab and bevacizumab was initiated. Although a complete response was achieved, the therapy was discontinued due to grade 3 diarrhea and grade 2 colitis after the sixth course. Based on the stool analysis and culture, CECT, and colonoscopy, the diagnosis was atezolizumab-associated colitis. Diarrhea was controlled following the oral administration of 0.5 mg/kg/day of prednisolone, and atezolizumab-bevacizumab therapy was successfully reinitiated without recurrence of colitis. The management of irAEs is important for a significant survival benefit. Systemic chemotherapy with atezolizumab and bevacizumab can be resumed despite a grade 3 irAE due to atezolizumab.

1 citations

Journal ArticleDOI
Lei Gu, Chunhui Jiang, Chunjie Xu, Ye Liu, Hong Zhou 
TL;DR: A prognostic risk model of 8-genes signature, which exhibited strong stability regardless of external and internal validation is developed and proposed that this classifier can serve as a molecular diagnostic tool to assess the prognosis of colon cancer patients.
Abstract: Background: Colon cancer (COAD) has been identified as being among the most prevalent tumors globally and ranked the third major contributor to cancer-related mortality. COAD is a molecularly heterogeneous disease. There are great differences in clinical manifestations and prognosis among different molecular subtypes. Methods:379 TCGA-COAD samples were divided into four subtypes: primary proliferative, with collective, crypt-like, and EMT invasion. The differences among the four subtypes were analyzed from the multidimensional perspectives of immunity, genomic variation, and prognosis. The limma package was utilized to identify differentially expressed genes (DEGs) amongst different molecular subtypes. Phenotype-related coexpressed gene modules were identified using WGCNA. The polygenic prognosis model was created utilizing the lasso Cox analysis and verified by time-dependent subject operating characteristics (ROC). Results: There are some differences in prognosis, TMB and common gene variation, immune score, and immunotherapy/chemotherapy between proliferative and three invasive molecular subtypes. 846 differential genes (DEGs) were obtained by limma packet analysis. Differential gene analysis was utilized to screen the DEGs among distinct subtypes, which were significantly enriched in the pathways related to tumorigenesis and development. Co-expression network analysis found 46 co-expressed genes correlated with proliferative and three invasive phenotypes. Based on differentially co-expressed genes, we developed a prognostic risk model of 8-genes signature, which exhibited strong stability regardless of external and internal validation. RT-PCR experiments proved the expression of eight genes in tumor and normal samples. Conclusion: We have developed an eight-gene signature prognostic stratification system. Furthermore, we proposed that this classifier can serve as a molecular diagnostic tool to assess the prognosis of colon cancer patients.

1 citations