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Nair U, Rakestraw E, Beasley GM, O’Connor MH. Opportunities for Discovery Using Neoadjuvant Immune Checkpoint Blockade in Melanoma. Int J Mol Sci 2025; 26:2427. [PMID: 40141071 PMCID: PMC11942238 DOI: 10.3390/ijms26062427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/06/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Treatment of resectable advanced-stage melanoma with neoadjuvant immunotherapy is rapidly becoming the new standard of care due to significant improvements in event-free survival (EFS) compared to surgery first followed by immunotherapy. The level of responsiveness seen in patients receiving immune checkpoint inhibitors (ICIs) must be mechanistically understood not only for the standardization of treatment but also to advance the novel concept of personalized cancer immunotherapy. This review aims to elucidate markers of the tumor microenvironment (TME) and blood that can predict treatment outcome. Interestingly, the canonical proteins involved in the molecular interactions that immunotherapies aim to disrupt have not been consistent indicators of treatment response, which amplifies the necessity for further research on the predictive model. Other major discussions surrounding neoadjuvant therapy involve the higher-level investigation of ICI efficacy due to the ability to examine a post-treatment tumor molecularly and pathologically, which this review will also cover. As neoadjuvant ICI becomes the standard of care in advanced melanoma treatment, further research aiming to identify more predictive biomarkers of treatment response to advance medical decision-making and patient care should continue to be sought after.
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Affiliation(s)
| | | | - Georgia M. Beasley
- Department of Surgery, Duke University, Durham, NC 27710, USA; (U.N.); (E.R.); (M.H.O.)
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Liu H, Gou X, Tan Y, Fan Q, Chen J. Immunotherapy and delivery systems for melanoma. Hum Vaccin Immunother 2024; 20:2394252. [PMID: 39286868 PMCID: PMC11409522 DOI: 10.1080/21645515.2024.2394252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 08/01/2024] [Accepted: 08/15/2024] [Indexed: 09/19/2024] Open
Abstract
Melanoma is a highly malignant tumor of melanocyte origin that is prone to early metastasis and has a very poor prognosis. Early melanoma treatment modalities are mainly surgical, and treatment strategies for advanced or metastatic melanoma contain chemotherapy, radiotherapy, targeted therapy and immunotherapy. The efficacy of chemotherapy and radiotherapy has been unsatisfactory due to low sensitivity and strong toxic side effects. And targeted therapy is prone to drug resistance, so its clinical application is limited. Melanoma has always been the leader of immunotherapy for solid tumors, and how to maximize the role of immunotherapy and how to implement immunotherapy more accurately are still urgent to be explored. This review summarizes the common immunotherapies and applications for melanoma, illustrates the current research status of melanoma immunotherapy delivery systems, and discusses the advantages and disadvantages of each delivery system and its prospects for clinical application.
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Affiliation(s)
- Hui Liu
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xi Gou
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yuanfang Tan
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Qiuying Fan
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Juanjuan Chen
- Jiangxi Province Key Laboratory of Immunology and Inflammation, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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Garcia JP, Ho OA, Haider SA, Borna S, Gomez-Cabello CA, Forte AJ, Spaulding AC. Impact of Physician Specialty on Treatment Costs of Invasive Melanoma. Diseases 2024; 12:284. [PMID: 39589958 PMCID: PMC11592836 DOI: 10.3390/diseases12110284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/31/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
INTRODUCTION Melanoma is a deadly type of skin cancer that develops from melanocytes and can manifest on the skin or other regions of the body. Its incidence is increasing rapidly, with approximately 100,000 diagnoses and 7000 deaths per year in the US alone. We conducted a cross-sectional study with the aim of determining an association between the cost of care for invasive melanoma and the specialty involved in the treatment to adequately guide future treatment. METHODS We analyzed data from 3817 patients (2013-2018) using the Florida inpatient/outpatient dataset, CMS cost reports, and the National Plan and Provider Enumeration System. Covariates included age, sex, race/ethnicity, insurance type, region, county rurality, the number of procedures, the comorbidity index, obesity, metastatic cancer presence, hospital size, and physician volume. Multivariable mixed linear regression was used to analyze the data, and the cost was adjusted to the 2019 USD. RESULTS Dermatology had the largest decrease in the overall and outpatient costs compared to general surgery, followed by plastic surgery. The inpatient costs for dermatology and plastic surgery were lower than those for general surgery, but not significantly so. CONCLUSIONS The costs associated with surgical procedures may vary depending on the specialty of the physician treating the patient. Dermatology was associated with lower treatment costs for invasive melanoma compared to other specialties, indicating that physician specialty influences the cost of care.
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Affiliation(s)
- John P. Garcia
- Division of Plastic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Olivia A. Ho
- Division of Plastic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Syed Ali Haider
- Division of Plastic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Sahar Borna
- Division of Plastic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | | | - Antonio Jorge Forte
- Division of Plastic Surgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Center for Digital Health, Mayo Clinic, Rochester, MN 55905, USA
| | - Aaron C. Spaulding
- Department of Health Science Research, Mayo Clinic, Jacksonville, FL 32224, USA
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Wang YY, Song JJ. A case report of the diagnosis and treatment of immune checkpoint inhibitor-related encephalitis induced by camrelizumab. AME Case Rep 2024; 8:101. [PMID: 39380870 PMCID: PMC11459425 DOI: 10.21037/acr-24-58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 07/26/2024] [Indexed: 10/10/2024]
Abstract
Background Camrelizumab has been widely used in the treatment of various cancers, it is important to determine the side-effect of this drug and the corresponding treatment strategy. Case Description The current case report describes the clinic, diagnosis, treatment and prognosis of camrelizumab-related encephalitis. Camrelizumab was administrated to a 67-year-old man with squamous cell carcinoma (SCC), a form of non-small cell lung cancer (NSCLC). One month after the treatment, the patient showed typical encephalitis symptoms including systemic fatigue, numbness of extremities and walking instability. Furthermore, the total protein in cerebrospinal fluid (CSF) was significantly elevated (1,399 vs. normal range 120-600 mg/L). Importantly, magnetic resonance imaging showed there was no brain metastasis. The patient did not get better after two days of intravenous injection of thioctic acid (1.2 g) and cobamamide (1.5 mg) once daily. Therefore, this patient was diagnosed as camrelizumab-related encephalitis. Then, we put him on one-month regimen: oral taper corticoids (methylprednisolone, MP) at 500 mg (days 1-4), 120 mg (days 5-10) and 60 mg (days 11-15); MP was replaced with oral prednisone acetate at 30 mg (days 16-30). After the treatment, the total protein in CSF was decreased to 873 mg/L, and all of encephalitis-related symptom was completely lost. About one year after the onset of encephalitis, the patient showed no recurrence of neurological symptoms. Conclusions The present case proves the efficacy and safety of corticoids in the treatment of camrelizumab-related adverse effects.
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Affiliation(s)
- Ya-Yun Wang
- Department of Pharmacy, The First People’s Hospital of Jiashan, Jiaxing, China
| | - Jian-Jiang Song
- Department of Cardiovascular Medicine, The First People’s Hospital of Jiashan, Jiaxing, China
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Szadai L, Bartha A, Parada IP, Lakatos AI, Pál DM, Lengyel AS, de Almeida NP, Jánosi ÁJ, Nogueira F, Szeitz B, Doma V, Woldmar N, Guedes J, Ujfaludi Z, Pahi ZG, Pankotai T, Kim Y, Győrffy B, Baldetorp B, Welinder C, Szasz AM, Betancourt L, Gil J, Appelqvist R, Kwon HJ, Kárpáti S, Kuras M, Murillo JR, Németh IB, Malm J, Fenyö D, Pawłowski K, Horvatovich P, Wieslander E, Kemény LV, Domont G, Marko-Varga G, Sanchez A. Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts. Front Oncol 2024; 14:1428182. [PMID: 39015503 PMCID: PMC11249723 DOI: 10.3389/fonc.2024.1428182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 06/10/2024] [Indexed: 07/18/2024] Open
Abstract
Introduction While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Methods Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Results Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Discussion Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.
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Affiliation(s)
- Leticia Szadai
- Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
| | - Aron Bartha
- Department of Bioinformatics, Semmelweis University, Budapest, Hungary
- Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Indira Pla Parada
- Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - Alexandra I.T. Lakatos
- HCEMM-SU Translational Dermatology Research Group, Semmelweis University, Budapest, Hungary
- Department of Physiology, Semmelweis University, Budapest, Hungary
- Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary
| | - Dorottya M.P. Pál
- HCEMM-SU Translational Dermatology Research Group, Semmelweis University, Budapest, Hungary
- Department of Physiology, Semmelweis University, Budapest, Hungary
- Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary
| | - Anna Sára Lengyel
- HCEMM-SU Translational Dermatology Research Group, Semmelweis University, Budapest, Hungary
- Department of Physiology, Semmelweis University, Budapest, Hungary
- Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary
| | - Natália Pinto de Almeida
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, Lund, Sweden
- Chemistry Institute Federal, University of Rio de Janeiro, Rio de Janiero, Brazil
| | - Ágnes Judit Jánosi
- Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
| | - Fábio Nogueira
- Chemistry Institute Federal, University of Rio de Janeiro, Rio de Janiero, Brazil
| | - Beata Szeitz
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Viktória Doma
- Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary
| | - Nicole Woldmar
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, Lund, Sweden
- Chemistry Institute Federal, University of Rio de Janeiro, Rio de Janiero, Brazil
| | - Jéssica Guedes
- Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - Zsuzsanna Ujfaludi
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- Competence Centre of the Life Sciences Cluster of the Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
| | - Zoltán Gábor Pahi
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- Competence Centre of the Life Sciences Cluster of the Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
- Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Genome Integrity and DNA Repair Core Group, University of Szeged, Szeged, Hungary
| | - Tibor Pankotai
- Department of Pathology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary
- Competence Centre of the Life Sciences Cluster of the Centre of Excellence for Interdisciplinary Research, Development and Innovation, University of Szeged, Szeged, Hungary
- Hungarian Centre of Excellence for Molecular Medicine (HCEMM), Genome Integrity and DNA Repair Core Group, University of Szeged, Szeged, Hungary
| | - Yonghyo Kim
- Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Republic of Korea
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, Budapest, Hungary
- Research Centre for Natural Sciences, Institute of Molecular Life Sciences, Budapest, Hungary
| | - Bo Baldetorp
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Charlotte Welinder
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - A. Marcell Szasz
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Lazaro Betancourt
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - Jeovanis Gil
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - Roger Appelqvist
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - Ho Jeong Kwon
- Chemical Genomics Global Research Lab, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Sarolta Kárpáti
- Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary
| | - Magdalena Kuras
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, Lund, Sweden
| | | | - István Balázs Németh
- Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary
| | - Johan Malm
- Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - David Fenyö
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, United States
| | - Krzysztof Pawłowski
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Peter Horvatovich
- Analytical Biochemistry, Department of Pharmacy, University of Groningen, Groningen, Netherlands
| | - Elisabet Wieslander
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Lajos V. Kemény
- HCEMM-SU Translational Dermatology Research Group, Semmelweis University, Budapest, Hungary
- Department of Physiology, Semmelweis University, Budapest, Hungary
- Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary
| | - Gilberto Domont
- Chemistry Institute Federal, University of Rio de Janeiro, Rio de Janiero, Brazil
| | - György Marko-Varga
- Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, Lund, Sweden
- First Department of Surgery, Tokyo Medical University, Nishishinjiku, Shinjiku-ku, Tokyo, Japan
| | - Aniel Sanchez
- Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
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Finke C, Mohr P. BRAF V600E Metastatic Melanoma Journey: A Perspective from a Patient and his Oncologist. Adv Ther 2024; 41:2576-2585. [PMID: 38806993 PMCID: PMC11213783 DOI: 10.1007/s12325-024-02883-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 04/22/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUND This article is co-authored by a patient with BRAFV600E metastatic melanoma and his treating oncologist. CASE DESCRIPTION The patient describes how he coped with his diagnosis and treatment. He details the pathway of his melanoma treatment, which has spanned over 10 years, including surgical interventions, medical treatment, and participation in clinical trials. He relates his experience of living with the disease-and the adverse effects of treatment-in the long term. The clinical perspective of his treating oncologist reviews the diagnostic process and explains how the therapeutic options were selected for and with the patient. The oncologist also addresses the integration of the patient into clinical trials involving programmed death-1 (PD-1) inhibitors and BRAF/MEK inhibitors. Challenges related to the adverse effects that occurred and the personalised treatment of the patient are also discussed. Finally, the article evaluates current advances in treatment and future therapeutic approaches. CONCLUSIONS This case highlights the challenges of identifying which therapeutic options are most appropriate for individual patients with BRAFV600E metastatic melanoma.
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Affiliation(s)
| | - Peter Mohr
- Clinic of Dermatology, Elbe Klinikum Buxtehude, Am Krankenhaus 1, 21614, Buxtehude, Germany.
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Szadai L, Bartha A, Parada IP, Lakatos A, Pál D, Lengyel AS, de Almeida NP, Jánosi ÁJ, Nogueira F, Szeitz B, Doma V, Woldmar N, Guedes J, Ujfaludi Z, Pahi ZG, Pankotai T, Kim Y, Győrffy B, Baldetorp B, Welinder C, Szasz AM, Betancourt L, Gil J, Appelqvist R, Kwon HJ, Kárpáti S, Kuras M, Murillo JR, Németh IB, Malm J, Fenyö D, Pawłowski K, Horvatovich P, Wieslander E, Kemény LV, Domont G, MarkoVarga G, Sanchez A. Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.01.592032. [PMID: 38746333 PMCID: PMC11092593 DOI: 10.1101/2024.05.01.592032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making. Abstract Figure
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Bracamonte-Baran W, Kim ST. The Current and Future of Biomarkers of Immune Related Adverse Events. Rheum Dis Clin North Am 2024; 50:201-227. [PMID: 38670721 PMCID: PMC11232920 DOI: 10.1016/j.rdc.2024.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
Abstract
With their groundbreaking clinical responses, immune checkpoint inhibitors (ICIs) have ushered in a new chapter in cancer therapeutics. However, they are often associated with life-threatening or organ-threatening autoimmune/autoinflammatory phenomena, collectively termed immune-related adverse events (irAEs). In this review, we will first describe the mechanisms of action of ICIs as well as irAEs. Next, we will review biomarkers for predicting the development of irAEs or stratifying risks.
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Affiliation(s)
- William Bracamonte-Baran
- Department of Rheumatology, Allergy & Immunology, Yale University, 300 Cedar Street, TAC S541, New Haven, CT 06520, USA
| | - Sang T Kim
- Department of Rheumatology, Allergy & Immunology, Yale University, 300 Cedar Street, TAC S541, New Haven, CT 06520, USA.
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Knoedler L, Huelsboemer L, Hollmann K, Alfertshofer M, Herfeld K, Hosseini H, Boroumand S, Stoegner VA, Safi AF, Perl M, Knoedler S, Pomahac B, Kauke-Navarro M. From standard therapies to monoclonal antibodies and immune checkpoint inhibitors - an update for reconstructive surgeons on common oncological cases. Front Immunol 2024; 15:1276306. [PMID: 38715609 PMCID: PMC11074450 DOI: 10.3389/fimmu.2024.1276306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 04/05/2024] [Indexed: 05/23/2024] Open
Abstract
Malignancies represent a persisting worldwide health burden. Tumor treatment is commonly based on surgical and/or non-surgical therapies. In the recent decade, novel non-surgical treatment strategies involving monoclonal antibodies (mAB) and immune checkpoint inhibitors (ICI) have been successfully incorporated into standard treatment algorithms. Such emerging therapy concepts have demonstrated improved complete remission rates and prolonged progression-free survival compared to conventional chemotherapies. However, the in-toto surgical tumor resection followed by reconstructive surgery oftentimes remains the only curative therapy. Breast cancer (BC), skin cancer (SC), head and neck cancer (HNC), and sarcoma amongst other cancer entities commonly require reconstructive surgery to restore form, aesthetics, and functionality. Understanding the basic principles, strengths, and limitations of mAB and ICI as (neo-) adjuvant therapies and treatment alternatives for resectable or unresectable tumors is paramount for optimized surgical therapy planning. Yet, there is a scarcity of studies that condense the current body of literature on mAB and ICI for BC, SC, HNC, and sarcoma. This knowledge gap may result in suboptimal treatment planning, ultimately impairing patient outcomes. Herein, we aim to summarize the current translational endeavors focusing on mAB and ICI. This line of research may serve as an evidence-based fundament to guide targeted therapy and optimize interdisciplinary anti-cancer strategies.
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Affiliation(s)
- Leonard Knoedler
- Department of Plastic, Hand, and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Lioba Huelsboemer
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Katharina Hollmann
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Faculty of Medicine, University of Wuerzbuerg, Wuerzburg, Germany
| | - Michael Alfertshofer
- Division of Hand, Plastic and Aesthetic Surgery, Ludwig-Maximilians University Munich, Munich, Germany
| | - Konstantin Herfeld
- Department of Internal Medicine III (Oncology and Haematology), University Hospital Regensburg, Regensburg, Germany
- Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Helia Hosseini
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Sam Boroumand
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Viola A. Stoegner
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Burn Center, Hannover Medical School, Hannover, Germany
| | - Ali-Farid Safi
- Craniologicum, Center for Cranio-Maxillo-Facial Surgery, Bern, Switzerland
- Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Markus Perl
- Department of Internal Medicine III (Oncology and Haematology), University Hospital Regensburg, Regensburg, Germany
- Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Samuel Knoedler
- Department of Plastic, Hand, and Reconstructive Surgery, University Hospital Regensburg, Regensburg, Germany
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Bohdan Pomahac
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
| | - Martin Kauke-Navarro
- Division of Plastic Surgery, Department of Surgery, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, United States
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Casagrande S, Sopetto GB, Bertalot G, Bortolotti R, Racanelli V, Caffo O, Giometto B, Berti A, Veccia A. Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations. Cancers (Basel) 2024; 16:1440. [PMID: 38611115 PMCID: PMC11011060 DOI: 10.3390/cancers16071440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.
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Affiliation(s)
- Silvia Casagrande
- Unit of Neurology, Rovereto Hospital, Azienda Provinciale per i Servizi Sanitari-APSS, 38122 Trento, Italy; (S.C.); (B.G.)
| | - Giulia Boscato Sopetto
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
| | - Giovanni Bertalot
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Multizonal Unit of Pathology, APSS, 38122 Trento, Italy
| | - Roberto Bortolotti
- Unit of Rheumatology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy;
| | - Vito Racanelli
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Unit of Internal Medicine, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy
| | - Orazio Caffo
- Unit of Oncology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy; (O.C.); (A.V.)
| | - Bruno Giometto
- Unit of Neurology, Rovereto Hospital, Azienda Provinciale per i Servizi Sanitari-APSS, 38122 Trento, Italy; (S.C.); (B.G.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Department of Psychology and Cognitive Sciences (DIPSCO), University of Trento, 38122 Trento, Italy
| | - Alvise Berti
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Unit of Rheumatology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy;
| | - Antonello Veccia
- Unit of Oncology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy; (O.C.); (A.V.)
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11
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Hasegawa T, Noguchi S, Nakashima M, Miyai M, Goto M, Matsumoto Y, Torii S, Honda S, Shimizu S. Alternative autophagy dampens UVB-induced NLRP3 inflammasome activation in human keratinocytes. J Biol Chem 2024; 300:107173. [PMID: 38499149 PMCID: PMC11002869 DOI: 10.1016/j.jbc.2024.107173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 03/08/2024] [Accepted: 03/11/2024] [Indexed: 03/20/2024] Open
Abstract
Sunlight exposure results in an inflammatory reaction of the skin commonly known as sunburn, which increases skin cancer risk. In particular, the ultraviolet B (UVB) component of sunlight induces inflammasome activation in keratinocytes to instigate the cutaneous inflammatory responses. Here, we explore the intracellular machinery that maintains skin homeostasis by suppressing UVB-induced inflammasome activation in human keratinocytes. We found that pharmacological inhibition of autophagy promoted UVB-induced NLRP3 inflammasome activation. Unexpectedly, however, gene silencing of Atg5 or Atg7, which are critical for conventional autophagy, had no effect, whereas gene silencing of Beclin1, which is essential not only for conventional autophagy but also for Atg5/Atg7-independent alternative autophagy, promoted UVB-induced inflammasome activation, indicating an involvement of alternative autophagy. We found that damaged mitochondria were highly accumulated in UVB-irradiated keratinocytes when alternative autophagy was inhibited, and they appear to be recognized by NLRP3. Overall, our findings indicate that alternative autophagy, rather than conventional autophagy, suppresses UVB-induced NLRP3 inflammasome activation through the clearance of damaged mitochondria in human keratinocytes and illustrate a previously unknown involvement of alternative autophagy in inflammation. Alternative autophagy may be a new therapeutic target for sunburn and associated cutaneous disorders.
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Affiliation(s)
| | - Saori Noguchi
- Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | | | | | - Makiko Goto
- Shiseido Global Innovation Center, Yokohama, Japan
| | | | - Satoru Torii
- Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinya Honda
- Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shigeomi Shimizu
- Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
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12
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Reschke R, Deitert B, Enk AH, Hassel JC. The role of tissue-resident memory T cells as mediators for response and toxicity in immunotherapy-treated melanoma-two sides of the same coin? Front Immunol 2024; 15:1385781. [PMID: 38562921 PMCID: PMC10982392 DOI: 10.3389/fimmu.2024.1385781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 03/05/2024] [Indexed: 04/04/2024] Open
Abstract
Tissue-resident memory T cells (TRM cells) have become an interesting subject of study for antitumor immunity in melanoma and other solid tumors. In the initial phases of antitumor immunity, they maintain an immune equilibrium and protect against challenges with tumor cells and the formation of primary melanomas. In metastatic settings, they are a prime target cell population for immune checkpoint inhibition (ICI) because they highly express inhibitory checkpoint molecules such as PD-1, CTLA-4, or LAG-3. Once melanoma patients are treated with ICI, TRM cells residing in the tumor are reactivated and expand. Tumor killing is achieved by secreting effector molecules such as IFN-γ. However, off-target effects are also observed. Immune-related adverse events, such as those affecting barrier organs like the skin, can be mediated by ICI-induced TRM cells. Therefore, a detailed understanding of this memory T-cell type is obligatory to better guide and improve immunotherapy regimens.
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Affiliation(s)
- Robin Reschke
- Department of Dermatology, National Center for Tumor Diseases Heidelberg (NCT), Heidelberg, Germany
| | - Benjamin Deitert
- Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alex H. Enk
- Department of Dermatology, National Center for Tumor Diseases Heidelberg (NCT), Heidelberg, Germany
| | - Jessica C. Hassel
- Department of Dermatology, National Center for Tumor Diseases Heidelberg (NCT), Heidelberg, Germany
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13
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Zakariya F, Salem FK, Alamrain AA, Sanker V, Abdelazeem ZG, Hosameldin M, Tan JK, Howard R, Huang H, Awuah WA. Refining mutanome-based individualised immunotherapy of melanoma using artificial intelligence. Eur J Med Res 2024; 29:25. [PMID: 38183141 PMCID: PMC10768232 DOI: 10.1186/s40001-023-01625-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 12/25/2023] [Indexed: 01/07/2024] Open
Abstract
Using the particular nature of melanoma mutanomes to develop medicines that activate the immune system against specific mutations is a game changer in immunotherapy individualisation. It offers a viable solution to the recent rise in resistance to accessible immunotherapy alternatives, with some patients demonstrating innate resistance to these drugs despite past sensitisation to these agents. However, various obstacles stand in the way of this method, most notably the practicality of sequencing each patient's mutanome, selecting immunotherapy targets, and manufacturing specific medications on a large scale. With the robustness and advancement in research techniques, artificial intelligence (AI) is a potential tool that can help refine the mutanome-based immunotherapy for melanoma. Mutanome-based techniques are being employed in the development of immune-stimulating vaccines, improving current options such as adoptive cell treatment, and simplifying immunotherapy responses. Although the use of AI in these approaches is limited by data paucity, cost implications, flaws in AI inference capabilities, and the incapacity of AI to apply data to a broad population, its potential for improving immunotherapy is limitless. Thus, in-depth research on how AI might help the individualisation of immunotherapy utilising knowledge of mutanomes is critical, and this should be at the forefront of melanoma management.
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Affiliation(s)
- Farida Zakariya
- Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Nigeria
- Division of Experimental Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada
| | - Fatma K Salem
- Faculty of Veterinary Medicine, South Valley University, Qena, 83523, Egypt
| | | | - Vivek Sanker
- Research Assistant, Dept. Of Neurosurgery, Trivandrum Medical College, Trivandrum, India
| | - Zainab G Abdelazeem
- Division of Molecular Biology, Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt
| | | | | | - Rachel Howard
- School of Clinical Medicine, University of Cambridge, Cambridge, England
| | - Helen Huang
- Faculty of Medicine and Health Science, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Wireko Andrew Awuah
- Medical Institute, Sumy State University, Zamonstanksya 7, Sumy, 40007, Ukraine.
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14
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Fiorentino V, Pizzimenti C, Franchina M, Pepe L, Russotto F, Tralongo P, Micali MG, Militi GB, Lentini M. Programmed Cell Death Ligand 1 Immunohistochemical Expression and Cutaneous Melanoma: A Controversial Relationship. Int J Mol Sci 2024; 25:676. [PMID: 38203846 PMCID: PMC10779806 DOI: 10.3390/ijms25010676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/29/2023] [Accepted: 01/03/2024] [Indexed: 01/12/2024] Open
Abstract
Cutaneous melanoma (CM) is traditionally considered one of the most "immunogenic" tumors, eliciting a high immune response. However, despite the presence of tumor-infiltrating lymphocytes (TILs), melanoma cells use strategies to suppress antitumor immunity and avoid being eliminated by immune surveillance. The PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) axis is a well-known immune escape system adopted by neoplastic cells. Therefore, immunotherapy with PD-1 and PD-L1 inhibitors is quickly becoming the main treatment approach for metastatic melanoma patients. However, the clinical utility of PD-L1 expression assessment in CM is controversial, and the interpretation of PD-L1 scores in clinical practice is still a matter of debate. Nonetheless, the recent literature data show that by adopting specific PD-L1 assessment methods in melanoma samples, a correlation between the expression of such a biomarker and a positive response to PD-1-based immunotherapy can be seen. Our review aims to describe the state-of-the-art knowledge regarding the prognostic and predictive role of PD-L1 expression in CM while also referring to possible biological explanations for the variability in its expressions and related treatment responses.
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Affiliation(s)
- Vincenzo Fiorentino
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (M.F.); (L.P.); (F.R.); (M.G.M.); (M.L.)
| | - Cristina Pizzimenti
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy;
| | - Mariausilia Franchina
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (M.F.); (L.P.); (F.R.); (M.G.M.); (M.L.)
| | - Ludovica Pepe
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (M.F.); (L.P.); (F.R.); (M.G.M.); (M.L.)
| | - Fernanda Russotto
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (M.F.); (L.P.); (F.R.); (M.G.M.); (M.L.)
| | - Pietro Tralongo
- Department of Women, Children and Public Health Sciences, Catholic University of the Sacred Heart, Agostino Gemelli IRCCS University Hospital Foundation, 00168 Rome, Italy;
| | - Marina Gloria Micali
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (M.F.); (L.P.); (F.R.); (M.G.M.); (M.L.)
| | - Gaetano Basilio Militi
- Department of Sciences for Promotion of Health and Mother and Child Care, Anatomic Pathology, University of Palermo, 90133 Palermo, Italy;
| | - Maria Lentini
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (M.F.); (L.P.); (F.R.); (M.G.M.); (M.L.)
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15
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Lu Y, Li Q, Xu L, Zheng Y, Wang Y, Liu Y, Zhang R, Liao L, Dong J. Thyroid dysfunction induced by anti-PD-1 therapy is associated with a better progression-free survival in patients with advanced carcinoma. J Cancer Res Clin Oncol 2023; 149:16501-16510. [PMID: 37715029 PMCID: PMC10645623 DOI: 10.1007/s00432-023-05364-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 08/28/2023] [Indexed: 09/17/2023]
Abstract
PURPOSE Thyroid dysfunction is the most common immune-related adverse event during anti-programmed cell death 1 (anti-PD-1) therapy. In this study, we monitored patients with advanced malignant tumors who received anti-PD-1 therapy to observe the characteristic of anti-PD-1 therapy-induced thyroid dysfunction and its correlation with prognosis. METHODS Patients with advanced carcinoma treated with anti-PD-1 therapy were evaluated for thyroid function at baseline and after treatment initiation from August 2020 to March 2022. Seventy-three patients were finally included in the study. RESULTS Among these patients, 19 (26.03%) developed thyroid dysfunction after receiving anti-PD-1 therapy. Primary hypothyroidism and thyrotoxicosis were the most common clinical manifestation. Anti-PD-1-induced thyroid dysfunction occurred 63 (26-131) days after administration; thyrotoxicosis appeared earlier than primary hypothyroidism. In Kaplan-Meier survival analysis, the progression-free survival (PFS) of the thyroid dysfunction group was better than that of the no thyroid dysfunction group (227 (95% confidence interval (CI) 50.85-403.15) days vs 164 (95% CI 77.76-250.24) days, p = 0.026). Male patients had better PFS than female patients (213 (95% CI 157.74-268.26) days vs 74 (95% CI 41.23-106.77) days, p = 0.031). In cox proportional hazards regression model, anti-PD-1-induced thyroid dysfunction remained an independent predictor of better PFS (hazard ratio (HR) = 0.339(0.136-0.848), p = 0.021). CONCLUSION Thyroid dysfunction is a common immune-related adverse events in advanced cancer patients treated with anti-PD-1 therapy and predicts a better prognosis. TRIAL REGISTRATION This study was retrospectively registered with Trial ClinicalTrials.gov (NCT05593744) on October 25, 2022.
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Affiliation(s)
- Yiran Lu
- Department of Endocrinology, Qilu Hospital, Shandong University, Ji-Nan, China
| | - Qingchen Li
- Department of Medical Oncology, Qilu Hospital, Shandong University, Ji-Nan, China
| | - Lusi Xu
- Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Shandong University, Ji-Nan, China
| | - Yanqing Zheng
- Department of Medical Oncology, Qilu Hospital, Shandong University, Ji-Nan, China
| | - Yanchao Wang
- Department of Medical Oncology, Qilu Hospital, Shandong University, Ji-Nan, China
| | - Ying Liu
- Department of Endocrinology, Qilu Hospital, Shandong University, Ji-Nan, China
| | - Rui Zhang
- Department of Endocrinology, Qilu Hospital, Shandong University, Ji-Nan, China
| | - Lin Liao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Ji-Nan, China.
- Department of Endocrinology and Metabology, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Nephrology, Ji-Nan, China.
| | - Jianjun Dong
- Department of Endocrinology, Qilu Hospital, Shandong University, Ji-Nan, China.
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16
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Roetman JJ, Erwin MM, Rudloff MW, Favret NR, Detrés Román CR, Apostolova MKI, Murray KA, Lee TF, Lee YA, Philip M. Tumor-Reactive CD8+ T Cells Enter a TCF1+PD-1- Dysfunctional State. Cancer Immunol Res 2023; 11:1630-1641. [PMID: 37844197 PMCID: PMC10841346 DOI: 10.1158/2326-6066.cir-22-0939] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 05/25/2023] [Accepted: 10/13/2023] [Indexed: 10/18/2023]
Abstract
T cells recognize several types of antigens in tumors, including aberrantly expressed, nonmutated proteins, which are therefore shared with normal tissue and referred to as self/shared-antigens (SSA), and mutated proteins or oncogenic viral proteins, which are referred to as tumor-specific antigens (TSA). Immunotherapies such as immune checkpoint blockade (ICB) can activate T-cell responses against TSA, leading to tumor control, and also against SSA, causing immune-related adverse events (irAE). To improve anti-TSA immunity while limiting anti-SSA autoreactivity, we need to understand how tumor-specific CD8+ T cells (TST) and SSA-specific CD8+ T (SST) cells differentiate in response to cognate antigens during tumorigenesis. Therefore, we developed a genetic cancer mouse model in which we can track TST and SST differentiation longitudinally as liver cancers develop. We found that both TST and SST lost effector function over time, but while TST persisted long term and had a dysfunctional/exhausted phenotype (including expression of PD1, CD39, and TOX), SST exited cell cycle prematurely and disappeared from liver lesions. However, SST persisted in spleens in a dysfunctional TCF1+PD-1- state: unable to produce effector cytokines or proliferate in response to ICB targeting PD-1 or PD-L1. Thus, our studies identify a dysfunctional T-cell state occupied by T cells reactive to SSA: a TCF1+PD-1- state lacking in effector function, demonstrating that the type/specificity of tumor antigen may determine tumor-reactive T-cell differentiation.
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Affiliation(s)
- Jessica J. Roetman
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Megan M. Erwin
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Michael W. Rudloff
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Natalie R. Favret
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Carlos R. Detrés Román
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Minna K. I. Apostolova
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Kristen A. Murray
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Ting-Fang Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, Nashville, TN USA
| | - Youngmin A. Lee
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, Nashville, TN USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mary Philip
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center, Nashville, TN USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
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17
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Liao PF, Wang PY, Peng TR. Efficacy and Safety of Programmed Death-1/Programmed Death-Ligand 1 Inhibitor for Metastatic Urothelial Carcinoma: A Systematic Review and Meta-Analysis. Curr Oncol 2023; 30:9940-9952. [PMID: 37999142 PMCID: PMC10670843 DOI: 10.3390/curroncol30110722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/19/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023] Open
Abstract
Objective: The purpose of this study was to evaluate the efficacy and safety of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for the treatment of metastatic urothelial carcinoma (mUC). Methods: A literature search was conducted of PubMed, EMBASE, and the Cochrane Library and was limited to the English literature. Randomized controlled trials (RCTs) published up to July 2022 were considered for inclusion. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade ≥ 3 treatment-related AEs (TRAE). Subgroup analysis was performed based on the PD-L1 expression status, and the differences between first- and second-line PD-1/PD-L1 inhibitors were estimated. Results: We included five RCTs comprising 3584 patients in the analysis. Compared with chemotherapy alone, the use of PD-1/PD-L1 inhibitors as monotherapy did not significantly prolong OS [hazard ratios (HR), 0.90; 95% CI, 0.81-1.00] or PFS (HR, 1.12; 95% CI, 0.95-1.32). However, the PD-1/PD-L1 inhibitor combined with chemotherapy significantly improved both OS (HR, 0.85; 95% CI, 0.74-0.96) and PFS (HR, 0.80; 95% CI, 0.71-0.90). Additionally, subgroup analysis showed that in mUC with PD-L1 expression ≥ 5%, treatment with the PD-1/PD-L1 inhibitor alone did not reduce the risk of death. Safety analysis showed that the PD-1/PD-L1 inhibitor alone did not significantly increase the incidence rates of grade ≥ 3 TRAEs. Conclusions: The results show that use of the PD-1/PD-L1 inhibitor alone as first-line treatment is similar to chemotherapy in terms of both survival and response rates. However, the PD-1/PD-L1 inhibitor plus chemotherapy has a significant benefit in terms of PFS or OS. Nonetheless, more RCTs are warranted to evaluate efficiency and safety in the combination regimen of chemotherapy and PD-1/PD-L1 inhibitors.
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Affiliation(s)
| | | | - Tzu-Rong Peng
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan
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18
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Blum SM, Rouhani SJ, Sullivan RJ. Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses. Immunol Rev 2023; 318:167-178. [PMID: 37578634 DOI: 10.1111/imr.13262] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 06/26/2023] [Indexed: 08/15/2023]
Abstract
Immune checkpoint inhibitors (ICIs) are potentially life-saving cancer therapies that can trigger immune-related adverse events (irAEs). irAEs can impact any organ and range in their presentation from mild side effects to life-threatening complications. The relationship between irAEs and antitumor immune responses is nuanced and may depend on the irAE organ, the tumor histology, and the patient. While some irAEs likely represent an immune response against antigens shared between tumor cells and healthy tissues, other irAEs may be entirely unrelated to antitumor immune responses. Clinical observations suggest that low-grade irAEs have a positive association with responses to ICIs, but the correlation between severe irAEs and clinical benefit is less clear. Currently, severe irAEs are typically treated by interrupting or permanently discontinuing ICI treatment and administering empirically selected systemic immunosuppressive agents. However, these interventions could potentially diminish the antitumor effects of ICIs. Efforts to understand the mechanistic relationship between irAEs and the tumor microenvironment have yielded meaningful insights and nominated therapeutic targets for irAE management that may preserve or even boost ICI efficacy. We explore the clinical and molecular relationship between irAEs and antitumor immunity as well as the role that irAE treatments may play in shaping antitumor immune responses.
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Affiliation(s)
- Steven M Blum
- Massachusetts General Hospital, Cancer Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
- Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Sherin J Rouhani
- Massachusetts General Hospital, Cancer Center, Boston, Massachusetts, USA
| | - Ryan J Sullivan
- Massachusetts General Hospital, Cancer Center, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
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19
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Song L, Li C, Yu J, Yang Y, Tian X, Choo SW. The anti-cancer effect and mechanism of animal scale-derived extract on malignant melanoma cells. Sci Rep 2023; 13:12548. [PMID: 37532809 PMCID: PMC10397295 DOI: 10.1038/s41598-023-39742-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 07/30/2023] [Indexed: 08/04/2023] Open
Abstract
Melanoma is a type of cancer with abnormal proliferation of melanocytes and is one of the most diagnosed cancer types. In traditional Chinese medicine, pangolin scales have been used to treat various diseases, including human cancers. However, its efficacy has not been scientifically proven. Here we studied the anticancer effect and mechanism of pangolin scale extract (PSE) on melanoma cell lines using scientific approaches. Our cell viability assay shows that PSE exhibits up to approximately 50-80% inhibition on SK-MEL-103 and A375 melanoma cell lines. Mechanically, PSE inhibits melanoma cell proliferation, migration, and causes changes in cell morphology. The apoptosis assay showed a significant chromosomal condensation inside the PSE-treated melanoma cells. The sequencing and analysis of A375 melanoma cell transcriptomes revealed 3077 differentially expressed genes in the 6 h treatment group and 8027 differentially expressed genes in the 72 h treatment group. Transcriptome analysis suggests that PSE may cause cell cycle arrest in melanoma cells and promote apoptosis mainly by up-regulating the p53 signaling pathway and down-regulating the PI3K-Akt signaling pathway. In this study, the anticancer effect of PSE was demonstrated by molecular biological means. PSE shows a significant inhibition effect on melanoma cell proliferation and cell migration in vitro, causes cell cycle arrest and promotes apoptosis through p53 and PI3K-AKT pathways. This study provides better insights into the anti-cancer efficacy and underlying mechanism of PSE and a theoretical basis for mining anticancer compounds or the development of new treatments for melanoma in the future. It is worth noting that this study does not advocate the use of the pangolin scale for disease treatment, but only to confirm its usefulness from a scientific research perspective and to encourage subsequent research around the development of active compounds to replace pangolin scales to achieve the conservation of this endangered species.
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Affiliation(s)
- Lanni Song
- Wenzhou Municipal Key Lab for Applied Biomedical and Biopharmaceutical Informatics, College of Science and Technology, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China
- Zhejiang Bioinformatics International Science and Technology Cooperation Center, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China
| | - Chen Li
- Wenzhou Municipal Key Lab for Applied Biomedical and Biopharmaceutical Informatics, College of Science and Technology, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China
- Zhejiang Bioinformatics International Science and Technology Cooperation Center, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China
| | - Jia Yu
- Department of Biology, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou, 325060, Zhejiang Province, China
| | - Yixin Yang
- Wenzhou Municipal Key Lab for Applied Biomedical and Biopharmaceutical Informatics, College of Science and Technology, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China
- Zhejiang Bioinformatics International Science and Technology Cooperation Center, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China
- Department of Biology, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou, 325060, Zhejiang Province, China
| | - Xuechen Tian
- Wenzhou Municipal Key Lab for Applied Biomedical and Biopharmaceutical Informatics, College of Science and Technology, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China.
- Zhejiang Bioinformatics International Science and Technology Cooperation Center, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China.
| | - Siew Woh Choo
- Wenzhou Municipal Key Lab for Applied Biomedical and Biopharmaceutical Informatics, College of Science and Technology, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China.
- Zhejiang Bioinformatics International Science and Technology Cooperation Center, Wenzhou-Kean University, Wenzhou, 325060, Zhejiang Province, China.
- Department of Biology, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou, 325060, Zhejiang Province, China.
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Cao T, Zhou X, Wu X, Zou Y. Cutaneous immune-related adverse events to immune checkpoint inhibitors: from underlying immunological mechanisms to multi-omics prediction. Front Immunol 2023; 14:1207544. [PMID: 37497220 PMCID: PMC10368482 DOI: 10.3389/fimmu.2023.1207544] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 06/05/2023] [Indexed: 07/28/2023] Open
Abstract
The development of immune checkpoint inhibitors (ICIs) has dramatically altered the landscape of therapy for multiple malignancies, including urothelial carcinoma, non-small cell lung cancer, melanoma and gastric cancer. As part of their anti-tumor properties, ICIs can enhance susceptibility to inflammatory side effects known as immune-related adverse events (irAEs), in which the skin is one of the most commonly and rapidly affected organs. Although numerous questions still remain unanswered, multi-omics technologies have shed light into immunological mechanisms, as well as the correlation between ICI-induced activation of immune systems and the incidence of cirAE (cutaneous irAEs). Therefore, we reviewed integrated biological layers of omics studies combined with clinical data for the prediction biomarkers of cirAEs based on skin pathogenesis. Here, we provide an overview of a spectrum of dermatological irAEs, discuss the pathogenesis of this "off-tumor toxicity" during ICI treatment, and summarize recently investigated biomarkers that may have predictive value for cirAEs via multi-omics approach. Finally, we demonstrate the prognostic significance of cirAEs for immune checkpoint blockades.
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Van Mol P, Donders E, Lambrechts D, Wauters E. Immune checkpoint biology in health & disease: Immune checkpoint biology and autoimmunity in cancer patients. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 382:181-206. [PMID: 38225103 DOI: 10.1016/bs.ircmb.2023.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
Immune checkpoints (ICs) play a central role in maintaining immune homoeostasis. The discovery that tumours use this physiological mechanism to avoid elimination by the immune system, opened up avenues for therapeutic targeting of ICs as a novel way of treating cancer. However, this therapy a new array of autoimmune side effects, termed immune-related adverse events (irAEs). In this narrative review, we first recapitulate the physiological function of ICs that are approved targets for cancer immunotherapy (CTLA-4, PD-(L)1 and LAG-3), as the groundwork to critically discuss current knowledge on irAEs. Specifically, we summarize clinical aspects and examine a molecular classification and predisposing factors of irAEs. Finally, we discuss irAE treatment, particularly emphasizing how molecular knowledge is changing the current treatment paradigm.
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Affiliation(s)
- Pierre Van Mol
- VIB - CCB Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium; Pneumology - Respiratory Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Elena Donders
- VIB - CCB Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium; Pneumology - Respiratory Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Diether Lambrechts
- VIB - CCB Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium
| | - Els Wauters
- Pneumology - Respiratory Oncology, University Hospitals Leuven, Leuven, Belgium.
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Manzari Tavakoli G, Mirzapour MH, Razi S, Rezaei N. Targeting ferroptosis as a cell death pathway in Melanoma: From molecular mechanisms to skin cancer treatment. Int Immunopharmacol 2023; 119:110215. [PMID: 37094541 DOI: 10.1016/j.intimp.2023.110215] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 03/30/2023] [Accepted: 04/17/2023] [Indexed: 04/26/2023]
Abstract
Melanoma, the most aggressive form of human skin cancer, has been under investigation to reach the most efficient treatment. Surgical resection for early-diagnosed primary melanoma, targeted therapies, and immune checkpoint inhibitors for advanced/metastatic melanoma is the best clinical approach. Ferroptosis, a newly identified iron-dependent cell death pathway, which is morphologically and biochemically different from apoptosis and necrosis, has been reported to be involved in several cancers. Ferroptosis inducers could provide therapeutic options in case of resistance to conventional therapies for advanced/metastatic melanoma. Recently developed ferroptosis inducers, MEK and BRAF inhibitors, miRNAs such as miR-137 and miR-9, and novel strategies for targeting major histocompatibility complex (MHC) class II in melanoma can provide new opportunities for melanoma treatment. Combining ferroptosis inducers with targeted therapies or immune checkpoint inhibitors increases patient response rates. Here we review the mechanisms of ferroptosis and its environmental triggers. We also discuss the pathogenesis and current treatments of melanoma. Moreover, we aim to elucidate the relationship between ferroptosis and melanoma and ferroptosis implications to develop new therapeutic strategies against melanoma.
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Affiliation(s)
- Gita Manzari Tavakoli
- Department of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mohammad Hossein Mirzapour
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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Zhang H, Shi Y, Ying J, Chen Y, Guo R, Zhao X, Jia L, Xiong J, Jiang F. A bibliometric and visualized research on global trends of immune checkpoint inhibitors related complications in melanoma, 2011-2021. Front Endocrinol (Lausanne) 2023; 14:1164692. [PMID: 37152956 PMCID: PMC10158729 DOI: 10.3389/fendo.2023.1164692] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 03/31/2023] [Indexed: 05/09/2023] Open
Abstract
BACKGROUND Melanoma is a malignant tumor that originates from the canceration of melanocytes with a high rate of invasiveness and lethality. Immune escape has been regarded as an important mechanism for tumor development, while the treatment of immune checkpoint inhibitors (ICIs) is beneficial in restoring and enhancing the body's anti-tumor immune response to kill tumor cells. To date, ICIs therapy has achieved remarkable efficacy in treating melanoma patients. Despite the significant clinical benefits of ICIs, multiple complications such as rashes, thyroiditis, and colitis occur in melanoma patients. In this study, we aim to explore the development process and trends in the field of ICIs-related complications in melanoma, analyze current hot topics, and predict future research directions. METHODS We screened the most relevant literatures on ICIs-related complications in melanoma from 2011 to 2021 in the Web of Science Core Collection (WoSCC). Using VOSviewer, CiteSpace and R language packages, we analyzed the research trends in this field. RESULTS A total of 1,087 articles were screened, and the USA had the highest number of publications (publications = 454, citations = 60,483), followed by Germany (publications = 155, citations = 27,743) and Italy (publications = 139, citations = 27,837). The Memorial Sloan Kettering Cancer Center had the most publications, but the Angeles Clinic and Research Institute had the highest average citation rate. Lancet oncology (IF, 2021 = 54.43) was the most prominent of all journals in terms of average citation rate. Reference and keyword cluster analysis revealed that anti-tumor efficacy, adjuvant treatment, clinical response, clinical outcome, etc. were the hotspots and trends of research in recent years. CONCLUSIONS This study offers a comprehensive summary and analysis of global research trends on ICIs-related complications in melanoma. Over the past decade, there has been a significant increase in the number of publications on this topic. However, the safety and benefits of retreatment after the recovery of ICIs-related complications remain unknown. Therefore,the establishment of related prediction models, as well as the immunotherapy of melanoma with ICIs in combination with other adjuvant therapies, are future research hotspots.
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Affiliation(s)
- Hongyi Zhang
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yanlong Shi
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jianghui Ying
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yi Chen
- Department of Biotechnology, The China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Rong Guo
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xin Zhao
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lingling Jia
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jiachao Xiong
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Fei Jiang
- Department of General Surgery, Fuyang Hospital of Anhui Medical University, Fuyang, China
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Ibrahim YS, Amin AH, Jawhar ZH, Alghamdi MA, Al-Awsi GRL, Shbeer AM, Al-Ghamdi HS, Gabr GA, Ramírez-Coronel AA, Almulla AF. "To be or not to Be": Regulatory T cells in melanoma. Int Immunopharmacol 2023; 118:110093. [PMID: 37023699 DOI: 10.1016/j.intimp.2023.110093] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 03/21/2023] [Accepted: 03/22/2023] [Indexed: 04/08/2023]
Abstract
In spite of progresses in the therapy of different malignancies, melanoma still remains as one of lethal types of skin tumor. Melanoma is almost easily treatable by surgery alone with higher overall survival rates when it is diagnosed at early stages. However, survival rates are decreased remarkably upon survival if the tumor is progressed to advanced metastatic stages. Immunotherapeutics have been prosperous in the development of anti-tumor responses in patients with melanoma through promotion of the tumor-specific effector T cells in vivo; nonetheless, suitable clinical outcomes have not been satisfactory. One of the underlying causes of the unfavorable clinical outcomes might stem from adverse effects of regulatory T (Treg) cell, which is a prominent mechanism of tumor cells to escape from tumor-specific immune responses. Evidence shows that a poor prognosis and low survival rate in patients with melanoma can be attributed to a higher Treg cell number and function in these subjects. As a result, to promote melanoma-specific anti-tumor responses, depletion of Treg cells appears to be a promising approach; even though the clinical efficacy of different approaches to attain appropriate Treg cell depletion has been inconsistent. Here in this review, the main purpose is to assess the role of Treg cells in the initiation and perpetuation of melanoma and to discuss effective strategies for Treg cell modulation with the aim of melanoma therapy.
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Affiliation(s)
- Yousif Saleh Ibrahim
- Department of Medical Laboratory Techniques, Al-maarif University College, Ramadi, Al-Anbar, Iraq
| | - Ali H Amin
- Deanship of Scientific Research, Umm Al-Qura University, Makkah 21955, Saudi Arabia; Zoology Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
| | - Zanko Hassan Jawhar
- Department of Medical Laboratory Science, College of Health Sciences, Lebanese French University, Erbil, Kurdistan Region, Iraq; Clinical Biochemistry Department, College of Health Sciences, Hawler Medical University, Erbil, Kurdistan Region, Iraq
| | - Mohammad A Alghamdi
- Internal Medicine Department, Faculty of Medicine, Albaha University, Saudi Arabia
| | | | - Abdullah M Shbeer
- Department of Surgery, Faculty of Medicine, Jazan University, Jazan 45142, Saudi Arabia
| | - Hasan S Al-Ghamdi
- Internal Medicine Department, Division of Dermatology, Faculty of Medicine, Albaha University, Albaha City, Saudi Arabia
| | - Gamal A Gabr
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia; Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center, Giza, Egypt.
| | - Andrés Alexis Ramírez-Coronel
- Catholic University of Cuenca, Azogues Campus, Ecuador; University of Palermo, Buenos Aires, Argentina; National University of Education, Azogues, Ecuador; CES University, Colombia
| | - Abbas F Almulla
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
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Jiang N, Yu Y, Wu D, Wang S, Fang Y, Miao H, Ma P, Huang H, Zhang M, Zhang Y, Tang Y, Li N. HLA and tumour immunology: immune escape, immunotherapy and immune-related adverse events. J Cancer Res Clin Oncol 2023; 149:737-747. [PMID: 36662304 DOI: 10.1007/s00432-022-04493-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 11/22/2022] [Indexed: 01/21/2023]
Abstract
PURPOSE As molecules responsible for presenting antigens to T lymphocytes, leukocytes antigens (HLAs) play a vital role in cancer immunology. This review aims to provide current understanding of HLAs in tumour immunology. METHODS Perspectives on how HLA alterations may contribute to the immune escape of cancer cells and resistance to immunotherapy, and potential methods to overcome HLA defects were summarized. In addition, we discussed the potential association between HLA and immune-related adverse events (irAEs), which has not been reviewed elsewhere. RESULTS Downregulation, loss of heterogeneity and entire loss of HLAs are responsible for the immune escape of tumour cells. The strategies to overcome the HLA defects can be effective therapies of cancer. Compared with classical HLA-I, non-classical HLA-I molecules, such as HLA-E and HLA-G, appear to be more reliable predictors of prognosis, as they tend to play immunosuppressive roles in antitumor response. Relative diversified or high expression of classical HLA-I are potential predictors of favourable response of immunotherapy. Certain HLA types may be associated to enhanced affinity to self-antigen-mimicked tumour-antigens, thus may positively correlated to irAEs triggered by checkpoint inhibitors. CONCLUSIONS Further studies exploring the relationship between HLAs and cancer may not only lead to the development of novel therapies but also bring about better management of irAEs.
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Affiliation(s)
- Ning Jiang
- Department of Clinical Trials Center, Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yue Yu
- Department of Clinical Trials Center, Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Dawei Wu
- Department of Clinical Trials Center, Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Shuhang Wang
- Department of Clinical Trials Center, Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Yuan Fang
- Department of Clinical Trials Center, Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Huilei Miao
- Department of Clinical Trials Center, Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Peiwen Ma
- Department of Clinical Trials Center, Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Huiyao Huang
- Department of Clinical Trials Center, Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | | | - Yu Zhang
- Renke Beijing Biotechnology Co., Ltd, Beijing, China
| | - Yu Tang
- Department of Clinical Trials Center, Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
| | - Ning Li
- Department of Clinical Trials Center, Clinical Cancer Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
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Positron emission tomography molecular imaging to monitor anti-tumor systemic response for immune checkpoint inhibitor therapy. Eur J Nucl Med Mol Imaging 2023; 50:1671-1688. [PMID: 36622406 PMCID: PMC10119238 DOI: 10.1007/s00259-022-06084-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 12/08/2022] [Indexed: 01/10/2023]
Abstract
Immune checkpoint inhibitors (ICIs) achieve a milestone in cancer treatment. Despite the great success of ICI, ICI therapy still faces a big challenge due to heterogeneity of tumor, and therapeutic response is complicated by possible immune-related adverse events (irAEs). Therefore, it is critical to assess the systemic immune response elicited by ICI therapy to guide subsequent treatment regimens. Positron emission tomography (PET) molecular imaging is an optimal approach in cancer diagnosis, treatment effect evaluation, follow-up, and prognosis prediction. PET imaging can monitor metabolic changes of immunocytes and specifically identify immuno-biomarkers to reflect systemic immune responses. Here, we briefly review the application of PET molecular imaging to date of systemic immune responses following ICI therapy and the associated rationale.
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Lee SM, Lee S, Cho HW, Min KJ, Hong JH, Song JY, Lee JK, Lee NW. Application of Immune Checkpoint Inhibitors in Gynecological Cancers: What Do Gynecologists Need to Know before Using Immune Checkpoint Inhibitors? Int J Mol Sci 2023; 24:974. [PMID: 36674491 PMCID: PMC9865129 DOI: 10.3390/ijms24020974] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/30/2022] [Accepted: 12/30/2022] [Indexed: 01/06/2023] Open
Abstract
Standard treatments for gynecological cancers include surgery, chemotherapy, and radiation therapy. However, there are limitations associated with the chemotherapeutic drugs used to treat advanced and recurrent gynecological cancers, and it is difficult to identify additional treatments. Therefore, immune checkpoint inhibitor (ICI) therapy products, including PD-1/PD-L1 inhibitors and CTLA-4 inhibitors, are in the spotlight as alternatives for the treatment of advanced gynecological cancers. Although the ICI monotherapy response rate in gynecological cancers is lower than that in melanoma or non-small cell lung cancer, the response rates are approximately 13-52%, 7-22%, and 4-17% for endometrial, ovarian, and cervical cancers, respectively. Several studies are being conducted to compare the outcomes of combining ICI therapy with chemotherapy, radiation therapy, and antiangiogenesis agents. Therefore, it is critical to determine the mechanism underlying ICI therapy-mediated anti-tumor activity and its application in gynecological cancers. Additionally, understanding the possible immune-related adverse events induced post-immunotherapy, as well as the appropriate management of diagnosis and treatment, are necessary to create a quality environment for immunotherapy in patients with gynecological cancers. Therefore, in this review, we summarize the ICI mechanisms, ICIs applied to gynecological cancers, and appropriate diagnosis and treatment of immune-related side effects to help gynecologists treat gynecological cancers using immunotherapy.
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Affiliation(s)
- Seon-Mi Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Koreadae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Sanghoon Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Koreadae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Hyun-Woong Cho
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 148, Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea
| | - Kyung-Jin Min
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 123, Jeokgeum-ro, Danwon-gu, Ansan-si 15355, Gyeonggi-do, Republic of Korea
| | - Jin-Hwa Hong
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 148, Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea
| | - Jae-Yun Song
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Koreadae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Jae-Kwan Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 148, Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea
| | - Nak-Woo Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 123, Jeokgeum-ro, Danwon-gu, Ansan-si 15355, Gyeonggi-do, Republic of Korea
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Hu X, Wang L, Shang B, Wang J, Sun J, Liang B, Su L, You W, Jiang S. Immune checkpoint inhibitor-associated toxicity in advanced non-small cell lung cancer: An updated understanding of risk factors. Front Immunol 2023; 14:1094414. [PMID: 36949956 PMCID: PMC10025397 DOI: 10.3389/fimmu.2023.1094414] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 02/20/2023] [Indexed: 03/08/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs), such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, etc, have revolutionized cancer treatment strategies, including non-small cell lung cancer (NSCLC). While these immunotherapy agents have achieved durable clinical benefits in a subset of NSCLC patients, they bring in a variety of immune-related adverse events (irAEs), which involve cardiac, pulmonary, gastrointestinal, endocrine and dermatologic system damage, ranging from mild to life-threatening. Thus, there is an urgent need to better understand the occurrence of irAEs and predict patients who are susceptible to those toxicities. Herein, we provide a comprehensive review of what is updated about the clinical manifestations, mechanisms, predictive biomarkers and management of ICI-associated toxicity in NSCLC. In addition, this review also provides perspective directions for future research of NSCLC-related irAEs.
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Affiliation(s)
- Xiangxiao Hu
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Lina Wang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Department of Respiratory and Critical Care Medicine, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bin Shang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Junren Wang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Jian Sun
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Bin Liang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Lili Su
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Wenjie You
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- *Correspondence: Wenjie You, ; Shujuan Jiang,
| | - Shujuan Jiang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, China
- Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Wenjie You, ; Shujuan Jiang,
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Yu Z, Zhu H, Chen H, Zhu L, Liao X. Gastrointestinal perforation associated with novel antineoplastic agents: A real-world study based on the FDA Adverse Event Reporting System. JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIETE CANADIENNE DES SCIENCES PHARMACEUTIQUES 2023; 26:11235. [PMID: 36942297 PMCID: PMC9990630 DOI: 10.3389/jpps.2023.11235] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/26/2023] [Indexed: 02/17/2023]
Abstract
Purpose: Gastrointestinal perforation (GIP) is a fatal adverse event (AE). The AE of GIP induced by novel antineoplastic agents has attracted attention recently. We aimed to explore the AE signals of GIP related to novel antineoplastic agents comprehensively based on the FDA Adverse Event Reporting System (FAERS). Methods: The FAERS database containing 71 quarters of records was used for analysis. Reporting odds ratio (ROR), information component (IC), and empirical Bayesian geometric mean (EBGM) were utilized to evaluate the signals of GIP associated with novel antineoplastic drugs. Standardization of drug names was by employing MedEx-UIMA software and Python. Data analysis and visualization were performed using MySQL Workbench and R software. Results: After cleaning and handling the data, 5226 GIP cases were identified that were associated with new antineoplastic medications, where these agents were the main suspected contributors. A total of 37 novel antineoplastic drugs were detected with signals of GIP for ROR and IC. Only 22 drugs showed statistically significant signals for EBGM. We found the GIP signals of 22 novel antineoplastic drugs overlapped for the 3 indicators, including anti-vascular endothelial growth factor/vascular endothelial growth factor receptor, anti-endothelial growth factor receptor, immune checkpoint inhibitors, and so on. Conclusion: The potential risk of GIP associated with several novel antineoplastic agents was identified through data mining, which provided valuable information on the safety risks associated with GIP among these drugs. The potential threat of GIP should be recognized and managed properly when using these novel antineoplastic agents.
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Shi F, Xue R, Xu H, Mei F, Bao X, Dou J, Zhao F. Mucin 1 downregulation decreases the anti-tumor effects of melanoma vaccine. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1361. [PMID: 36660692 PMCID: PMC9843407 DOI: 10.21037/atm-22-6170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/13/2022] [Indexed: 12/30/2022]
Abstract
Background Immunotherapy-based approaches are important breakthroughs with potential treatment benefits for melanoma patients. Mucin 1 (MUC1) is significantly upregulated in melanoma relative to normal cells. It has been reported that MUC1 influences cancer cell proliferation, apoptosis, invasion, and metastasis.The study aimed to explore the effect of MUC1 knockdown on the biological characteristics of the melanoma cell line B16F10 and evaluate whether MUC1 is an effective candidate target antigen for melanoma vaccine development. Methods First, lentiviral vector-mediated short hairpin RNA (shRNA) was used to knockdown MUC1 in B16F10 cells (shMUC1-B16F10 cells). Next, we examined epithelial-mesenchymal transition (EMT), migration, proliferative capacity, clone formation, and distribution of cell cycle in shMUC1-B16F10 cells. Finally, the vaccine was prepared by repeated freeze-thawing of the shMUC1-B16F10 cells and used to subcutaneously immunize C57BL/6 mice, which were then challenged using B16F10 cells 10 days after the final vaccination. Results It was revealed that shMUC1 suppressed B16F10 proliferative and colony formation capacity, induced the arrest of cell cycle in the G0/G1 phase, and adjusted the expression of EMT-associated factors. MUC1 downregulation markedly suppressed the effect of B16F10 vaccine against melanoma in a mouse model. As compared with B16F10-vaccinated mice, B16F10-vaccinated mice in which MUC1 was silenced had reduced natural killer (NK) cytotoxicity, lower production of interferon-γ (IFN-γ), anti-MUC1 antibodies, perforin, granzyme B, and elevated tumor growth factor-β (TGF-β) level. Conclusions MUC1 has strong melanoma vaccine immunogenicity, and induces the host's anti-tumor reaction. MUC1 knockdown inhibits the immune activity of B16F10 cell vaccine and anti-melanoma effect, suggesting the MUC1 is an important candidate target antigen of the melanoma vaccine.
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Affiliation(s)
- Fangfang Shi
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, China;,Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Rui Xue
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, China
| | - Hui Xu
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, China
| | - Feng Mei
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, China
| | - Xueyang Bao
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, China
| | - Jun Dou
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, China
| | - Fengshu Zhao
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, China
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Immune checkpoint blockade in melanoma: Advantages, shortcomings and emerging roles of the nanoparticles. Int Immunopharmacol 2022; 113:109300. [DOI: 10.1016/j.intimp.2022.109300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/05/2022]
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Chen N, Qian MJ, Zhang RH, Gao QQ, He CC, Yao YK, Zhou JY, Zhou H. Tislelizumab-related enteritis successfully treated with adalimumab: A case report. World J Clin Cases 2022; 10:10186-10192. [PMID: 36246838 PMCID: PMC9561571 DOI: 10.12998/wjcc.v10.i28.10186] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/17/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND With programmed death-1 (PD-1) inhibitors becoming the standard treatment for lung cancer, PD-1-related adverse reactions and treatment have gradually become prominent.
CASE SUMMARY First reported case of tislelizumab-related enteritis successfully treated with adalimumab 40mg every 2 wk for 3 times in an advanced lung cancer patient who received first-line tislelizumab/pemetrexed/carboplatin for 4 cycles. The patient continued receiving the treatment of pemetrexed/carboplatin after symptoms, abdominal computed tomography and colonoscopy improved, significant diarrhea was not occurred.
CONCLUSION Adalimumab can be an effective treatment option for patients with PD-1 antibody related enteritis if they do not respond well to glucocorticoid treatment.
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Affiliation(s)
- Na Chen
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Min-Jia Qian
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Department of Critical Care Medicine, Zhuji People’s Hospital, Shaoxing 311800, Zhejiang Province, China
| | - Ru-Hui Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Qi-Qi Gao
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Chao-Chao He
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
- Department of Pharmacy, Yiwu Central Hospital, Jinhua 322000, Zhejiang Province, China
| | - Ya-Ke Yao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Ying Zhou
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Hua Zhou
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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Tang J, Gong Y, Ma X. Bispecific Antibodies Progression in Malignant Melanoma. Front Pharmacol 2022; 13:837889. [PMID: 35401191 PMCID: PMC8984188 DOI: 10.3389/fphar.2022.837889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/28/2022] [Indexed: 02/05/2023] Open
Abstract
The discovery of oncogenes and immune checkpoints has revolutionized the treatment of melanoma in the past 10 years. However, the current PD-L1 checkpoints lack specificity for tumors and target normal cells expressing PD-L1, thus reducing the efficacy on malignant melanoma and increasing the side effects. In addition, the treatment options for primary or secondary drug-resistant melanoma are limited. Bispecific antibodies bind tumor cells and immune cells by simultaneously targeting two antigens, enhancing the anti-tumor targeting effect and cytotoxicity and reducing drug-resistance in malignant melanoma, thus representing an emerging strategy to improve the clinical efficacy. This review focused on the treatment of malignant melanoma by bispecific antibodies and summarized the effective results of the experiments that have been conducted, also discussing the different aspects of these therapies. The role of the melanoma epitopes, immune cell activation, cell death and cytotoxicity induced by bispecific antibodies were evaluated in the clinical or preclinical stage, as these therapies appear to be the most suitable in the treatment of malignant melanoma.
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Affiliation(s)
- Juan Tang
- Department of Oncology, West China Hospital of Sichuan University, Chengdu, China
| | - Youling Gong
- Department of Oncology, West China Hospital of Sichuan University, Chengdu, China
| | - Xuelei Ma
- Department of Oncology, West China Hospital of Sichuan University, Chengdu, China
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Ghosh N, Bass AR. Checkpoint Inhibitor-Associated Autoimmunity: What a Rheumatologist Needs to Know. J Clin Rheumatol 2022; 28:e659-e666. [PMID: 31743272 DOI: 10.1097/rhu.0000000000001209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Nilasha Ghosh
- From the Division of Rheumatology, Department of Medicine, Hospital for Special Surgery; and Weill Cornell Medicine, New York, NY
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35
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Tong S, Cinelli MA, El-Sayed NS, Huang H, Patel A, Silverman RB, Yang S. Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS). Sci Rep 2022; 12:1701. [PMID: 35105915 PMCID: PMC8807785 DOI: 10.1038/s41598-022-05394-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 12/24/2021] [Indexed: 02/07/2023] Open
Abstract
Interferon-gamma (IFN-γ) is shown to stimulate melanoma development and progression. However, the underlying mechanism has not been completely defined. Our study aimed to determine the role of neuronal nitric oxide synthase (nNOS)-mediated signaling in IFN-γ-stimulated melanoma progression and the anti-melanoma effects of novel nNOS inhibitors. Our study shows that IFN-γ markedly induced the expression levels of nNOS in melanoma cells associated with increased intracellular nitric oxide (NO) levels. Co-treatment with novel nNOS inhibitors effectively alleviated IFN-γ-activated STAT1/3. Further, reverse phase protein array (RPPA) analysis demonstrated that IFN-γ induced the expression of HIF1α, c-Myc, and programmed death-ligand 1 (PD-L1), in contrast to IFN-α. Blocking the nNOS-mediated signaling pathway using nNOS-selective inhibitors was shown to effectively diminish IFN-γ-induced PD-L1 expression in melanoma cells. Using a human melanoma xenograft mouse model, the in vivo studies revealed that IFN-γ increased tumor growth compared to control, which was inhibited by the co-administration of nNOS inhibitor MAC-3-190. Another nNOS inhibitor, HH044, was shown to effectively inhibit in vivo tumor growth and was associated with reduced PD-L1 expression levels in melanoma xenografts. Our study demonstrates the important role of nNOS-mediated NO signaling in IFN-γ-stimulated melanoma progression. Targeting nNOS using highly selective small molecular inhibitors is a unique and effective strategy to improve melanoma treatment.
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Affiliation(s)
- Shirley Tong
- Department of Pharmacy Practice, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, #297-Y, 9401 Jeronimo Road, Irvine, CA, 92618, USA
| | - Maris A Cinelli
- Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, and Center for Developmental Therapeutics, Northwestern University, Evanston, IL, 60208, USA
| | - Naglaa Salem El-Sayed
- Department of Pharmacy Practice, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, #297-Y, 9401 Jeronimo Road, Irvine, CA, 92618, USA
| | - He Huang
- Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, and Center for Developmental Therapeutics, Northwestern University, Evanston, IL, 60208, USA
| | - Anika Patel
- Department of Pharmacy Practice, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, #297-Y, 9401 Jeronimo Road, Irvine, CA, 92618, USA
| | - Richard B Silverman
- Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, and Center for Developmental Therapeutics, Northwestern University, Evanston, IL, 60208, USA.,Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Sun Yang
- Department of Pharmacy Practice, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, #297-Y, 9401 Jeronimo Road, Irvine, CA, 92618, USA.
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36
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Gameiro SF, Evans AM, Mymryk JS. The tumor immune microenvironments of HPV + and HPV - head and neck cancers. WIREs Mech Dis 2022; 14:e1539. [PMID: 35030304 DOI: 10.1002/wsbm.1539] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/24/2022]
Abstract
Human papillomaviruses (HPVs) are the etiological agent of a significant, and increasing, fraction of head and neck squamous cell carcinomas (HNSCC)-a heterogenous group of malignancies in the head and neck region. HPV infection accounts for approximately 25% of all cases, with the remainder typically caused by smoking and excessive alcohol consumption. These distinct etiologies lead to profound clinical and immunological differences between HPV-positive (HPV+ ) and HPV-negative (HPV- ) HNSCC, likely related to the expression of exogenous viral antigens in the HPV+ subtype. Specifically, HPV+ HNSCC patients generally exhibit better treatment response compared to those with HPV- disease, leading to a more favorable prognosis, with lower recurrence rate, and longer overall survival time. Importantly, a plethora of studies have illustrated that the tumor immune microenvironment (TIME) of HPV+ HNSCC has a strikingly distinct immune composition to that of its HPV- counterpart. The HPV+ TIME is characterized as being immunologically "hot," with more immune infiltration, higher levels of T-cell activation, and higher levels of immunoregulation compared to the more immunologically "cold" HPV- TIME. In general, cancers with an immune "hot" TIME exhibit better treatment response and superior clinical outcomes in comparison to their immune "cold" counterparts. Indeed, this phenomenon has also been observed in HPV+ HNSCC patients, highlighting the critical role of the TIME in influencing prognosis, and further validating the use of cancer therapies that capitalize on the mobilization and/or modulation of the TIME. This article is categorized under: Cancer > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Steven F Gameiro
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Andris M Evans
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Joe S Mymryk
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.,Department of Otolaryngology, The University of Western Ontario, London, Ontario, Canada.,Department of Oncology, The University of Western Ontario, London, Ontario, Canada.,London Regional Cancer Program, Lawson Health Research Institute, London, Ontario, Canada
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37
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Vučinić D, Grahovac M, Grahovac B, Vitezić BM, Kovač L, Belušić-Gobić M, Zamolo G. PD-L1 expression is regulated by microphthalmia-associated transcription factor (MITF) in nodular melanoma. Pathol Res Pract 2022; 229:153725. [DOI: 10.1016/j.prp.2021.153725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 10/19/2022]
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38
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Motofei IG. Nobel Prize for immune checkpoint inhibitors, understanding the immunological switching between immunosuppression and autoimmunity. Expert Opin Drug Saf 2021; 21:599-612. [PMID: 34937484 DOI: 10.1080/14740338.2022.2020243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs) are a revolutionary form of immunotherapy in cancer. However, the percentage of patients responding to therapy is relatively low, while adverse effects occur in a large number of patients. In addition, the therapeutic mechanisms of ICIs are not yet completely described. AREAS COVERED The initial view (articles published in PubMed, Scopus, Web of Science, etc.) was that ICIs increase tumor-specific immunity. Recent data (collected from the same databases) suggest that the ICIs pharmacotherapy actually extends beyond the topic of immune reactivity, including additional immune pathways, such as disrupting immunosuppression and increasing tumor-specific autoimmunity. Unfortunately, there is no clear delimitation between these specific autoimmune reactions that are therapeutically beneficial, and nonspecific autoimmune reactions/toxicity that can be extremely severe side effects. EXPERT OPINION Immune checkpoint mechanisms perform a non-selective immune regulation, maintaining a dynamic balance between immunosuppression and autoimmunity. By blocking these mechanisms, ICIs actually perform an immunological reset, decreasing immunosuppression and increasing tumor-specific immunity and predisposition to autoimmunity. The predisposition to autoimmunity induces both side effects and beneficial autoimmunity. Consequently, further studies are necessary to maximize the beneficial tumor-specific autoimmunity, while reducing the counterproductive effect of associated autoimmune toxicity.
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Affiliation(s)
- Ion G Motofei
- Department of Surgery/ Oncology, Carol Davila University, Bucharest, Romania.,Department of Surgery/ Oncology, St. Pantelimon Hospital, Bucharest, Romania
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39
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Schilling HL, Glehr G, Kapinsky M, Ahrens N, Riquelme P, Cordero L, Bitterer F, Schlitt HJ, Geissler EK, Haferkamp S, Hutchinson JA, Kronenberg K. Development of a Flow Cytometry Assay to Predict Immune Checkpoint Blockade-Related Complications. Front Immunol 2021; 12:765644. [PMID: 34868015 PMCID: PMC8637156 DOI: 10.3389/fimmu.2021.765644] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 10/27/2021] [Indexed: 12/17/2022] Open
Abstract
Treatment of advanced melanoma with combined immune checkpoint inhibitor (ICI) therapy is complicated in up to 50% of cases by immune-related adverse events (irAE) that commonly include hepatitis, colitis and skin reactions. We previously reported that pre-therapy expansion of cytomegalovirus (CMV)-reactive CD4+ effector memory T cells (TEM) predicts ICI-related hepatitis in a subset of patients with Stage IV melanoma given αPD-1 and αCTLA-4. Here, we develop and validate a 10-color flow cytometry panel for reliably quantifying CD4+ TEM cells and other biomarkers of irAE risk in peripheral blood samples. Compared to previous methods, our new panel performs equally well in measuring CD4+ TEM cells (agreement = 98%) and is superior in resolving CD4+ CD197+ CD45RA- central memory T cells (TCM) from CD4+ CD197+ CD45RA+ naive T cells (Tnaive). It also enables us to precisely quantify CD14+ monocytes (CV = 6.6%). Our new “monocyte and T cell” (MoT) assay predicts immune-related hepatitis with a positive predictive value (PPV) of 83% and negative predictive value (NPV) of 80%. Our essential improvements open the possibility of sharing our predictive methods with other clinical centers. Furthermore, condensing measurements of monocyte and memory T cell subsets into a single assay simplifies our workflows and facilitates computational analyses.
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Affiliation(s)
| | - Gunther Glehr
- Institute of Functional Genomics and Statistical Bioinformatics, University of Regensburg, Regensburg, Germany
| | | | - Norbert Ahrens
- Medizinisches Versorgungszentrum (MVZ) for Laboratory Medicine Raubling, amedes Labor, Raubling, Germany.,Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Paloma Riquelme
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Laura Cordero
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Florian Bitterer
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Hans J Schlitt
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Edward K Geissler
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Sebastian Haferkamp
- Department of Dermatology, University Hospital Regensburg, Regensburg, Germany
| | - James A Hutchinson
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
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Liu X, Shi Y, Zhang D, Zhou Q, Liu J, Chen M, Xu Y, Zhao J, Zhong W, Wang M. Risk factors for immune-related adverse events: what have we learned and what lies ahead? Biomark Res 2021; 9:79. [PMID: 34732257 PMCID: PMC8565046 DOI: 10.1186/s40364-021-00314-8] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 07/08/2021] [Indexed: 12/18/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have heralded the advent of a new era in oncology by holding the promise of prolonged survival in severe and otherwise treatment-refractory advanced cancers. However, the remarkable antitumor efficacy of these agents is overshadowed by their potential for inducing autoimmune toxic effects, collectively termed immune-related adverse events (irAEs). These autoimmune adverse effects are often difficult to predict, possibly permanent, and occasionally fatal. Hence, the identification of risk factors for irAEs is urgently needed to allow for prompt therapeutic intervention. This review discusses the potential mechanisms through which irAEs arise and summarizes the existing evidence regarding risk factors associated with the occurrence of irAEs. In particular, we examined available data regarding the effect of a series of clinicopathological and demographic factors on the risk of irAEs.
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Affiliation(s)
- Xiaoyan Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China
| | - Yuequan Shi
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China
| | - Dongming Zhang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China
| | - Qing Zhou
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China
| | - Jia Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China
| | - Minjiang Chen
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China
| | - Yan Xu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China
| | - Jing Zhao
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China
| | - Wei Zhong
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China.
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No 1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China.
| | - Mengzhao Wang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China.
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No 1 Shuaifuyuan Wangfujing, Dongcheng District, 100730, Beijing, China.
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41
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The Price of Success: Immune-Related Adverse Events from Immunotherapy in Lung Cancer. Curr Oncol 2021; 28:4392-4407. [PMID: 34898551 PMCID: PMC8628657 DOI: 10.3390/curroncol28060373] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/19/2021] [Accepted: 10/31/2021] [Indexed: 12/19/2022] Open
Abstract
Cancer immunotherapy has the goal of enhancing a patient’s intrinsic immune processes in order to mount a successful immune response against tumor cells. Cancer cells actively employ tactics to evade, delay, alter, or attenuate the anti-tumor immune response. Immune checkpoint inhibitors (ICIs) modulate endogenous regulatory immune mechanisms to enhance immune system activation, and have become the mainstay of therapy in many cancer types. This activation occurs broadly and as a result, activation is supraphysiologic and relatively non-specific, which can lead to immune-related adverse events (irAEs), the frequency of which depends on the patient, the cancer type, and the specific ICI antibody. Careful assessment of patients for irAEs through history taking, physical exam, and routine laboratory assessments are key to identifying irAEs at early stages, when they can potentially be managed more easily and before progressing to higher grades or more serious effects. Generally, most patients with low grade irAEs are eligible for re-challenge with ICIs, and the use of corticosteroids to address an irAE is not associated with poorer patient outcomes. This paper reviews immune checkpoint inhibitors (ICIs) including their mechanisms of action, usage, associated irAEs, and their management.
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42
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Rea A, Anderson A, Moshiri A, Paulson K, Thompson JA, Kalus A. Eosinophilic fasciitis as a paraneoplastic syndrome in melanoma. JAAD Case Rep 2021; 17:49-51. [PMID: 34703864 PMCID: PMC8526906 DOI: 10.1016/j.jdcr.2021.09.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Affiliation(s)
- Andrea Rea
- Division of Dermatology, University of Washington, Seattle, Washington
| | - Alexis Anderson
- School of Medicine, University of Washington, Seattle, Washington
| | - Ata Moshiri
- Division of Dermatology, University of Washington, Seattle, Washington
| | - Kelly Paulson
- Swedish Cancer Institute Medical Oncology, Edmonds, Washington
| | - John A Thompson
- Division of Oncology, University of Washington, Seattle, Washington
| | - Andrea Kalus
- Division of Dermatology, University of Washington, Seattle, Washington
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43
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Han D, Tai Y, Hua G, Yang X, Chen J, Li J, Deng X. Melanocytes in black-boned chicken have immune contribution under infectious bursal disease virus infection. Poult Sci 2021; 100:101498. [PMID: 34695633 PMCID: PMC8554273 DOI: 10.1016/j.psj.2021.101498] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 08/03/2021] [Accepted: 09/16/2021] [Indexed: 12/20/2022] Open
Abstract
In black-boned chicken, melanocytes are widely distributed in their inner organs. However, the roles of these cells are not fully elucidated. In this study, we used 3-wk-old female Silky Fowl to investigate the functions of melanocytes under infection with infectious bursal disease virus (IBDV). We found the melanocytes in the bursa of Fabricius involved in IBDV infection shown as abundant melanin were transported into the nodule and lamina propria where obvious apoptotic cells and higher expression of BAX were detected. Genes related to the toll-like receptor (TLR) signaling pathway were highly detected by quantitative PCR, including TLR1, TLR3, TLR4, TLR15, myeloid differential protein-88, interferon-α, and interferon-β. We then isolated and infected primary melanocytes with IBDV in vitro and found that higher expressions of immune genes were detected at 24 and 48 h after infection; the upregulated innate and adaptive immune genes were involved in the pathogenesis of IBDV infection, including TLR3, TLR7, interleukin 15 (IL15), IL18, IL1rap, CD7, BG2, ERAP1, and SLA2. These changes in gene expression were highly associated with microtubule-based movement, antigen processing and presentation, defense against viruses, and innate immune responses. Our results indicated that the widely distributed melanocytes in Silky Fowl could migrate to play important innate immune roles during virus infection.
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Affiliation(s)
- Deping Han
- College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Yurong Tai
- Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture & Beijing Key Laboratory of Animal Genetic Improvement, China Agricultural University, Beijing 100193, China
| | - Guoying Hua
- Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture & Beijing Key Laboratory of Animal Genetic Improvement, China Agricultural University, Beijing 100193, China
| | - Xue Yang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture & Beijing Key Laboratory of Animal Genetic Improvement, China Agricultural University, Beijing 100193, China
| | - Jianfei Chen
- Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture & Beijing Key Laboratory of Animal Genetic Improvement, China Agricultural University, Beijing 100193, China
| | - Junying Li
- Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture & Beijing Key Laboratory of Animal Genetic Improvement, China Agricultural University, Beijing 100193, China
| | - Xuemei Deng
- Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture & Beijing Key Laboratory of Animal Genetic Improvement, China Agricultural University, Beijing 100193, China.
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44
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Liu X, Yi Y. Sintilimab plus sorafenib: a novel regimen for hepatocellular carcinoma. Immunotherapy 2021; 13:1387-1393. [PMID: 34665016 DOI: 10.2217/imt-2021-0062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Hepatocellular carcinoma is one of the most common malignant tumors in China and is also a major cause of cancer deaths worldwide. Recent advances in immunotherapy have identified new treatments in which immunotherapy can be combined with antiangiogenic therapy. We report a case of hepatocellular carcinoma with a tumor thrombus at the inferior vena cava-right atrium junction and multiple lung metastases after a multiple-course treatment. Treatment with sintilimab in combination with sorafenib led to a partial remission and immune-related hepatitis.
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Affiliation(s)
- Xuhong Liu
- The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.,Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Yong Yi
- Department of Liver surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital & Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, 200032, China
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45
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Millán-Esteban D, Peña-Chilet M, García-Casado Z, Manrique-Silva E, Requena C, Bañuls J, López-Guerrero JA, Rodríguez-Hernández A, Traves V, Dopazo J, Virós A, Kumar R, Nagore E. Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development. Cancers (Basel) 2021; 13:5219. [PMID: 34680367 PMCID: PMC8533762 DOI: 10.3390/cancers13205219] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/22/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF. The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1, ROS1, GNA11, and RAC1. We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.
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Affiliation(s)
- David Millán-Esteban
- School of Medicine, Universidad Católica de València San Vicente Mártir, 46001 Valencia, Spain;
- Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, 46009 Valencia, Spain; (Z.G.-C.); (J.A.L.-G.)
| | - María Peña-Chilet
- Clinical Bioinformatics Area, Fundación Progreso y Salud, Hospital Virgen del Rocío, 41013 Sevilla, Spain; (M.P.-C.); (J.D.)
- Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 41013 Sevilla, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocío, 41013 Sevilla, Spain;
| | - Zaida García-Casado
- Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, 46009 Valencia, Spain; (Z.G.-C.); (J.A.L.-G.)
| | - Esperanza Manrique-Silva
- Department of Dermatology, Fundación Instituto Valenciano de Oncología, 46009 Valencia, Spain; (E.M.-S.); (A.R.-H.)
| | - Celia Requena
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocío, 41013 Sevilla, Spain;
| | - José Bañuls
- Department of Dermatology, El Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital General Universitario de Alicante, 03010 Alicante, Spain;
| | - Jose Antonio López-Guerrero
- Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, 46009 Valencia, Spain; (Z.G.-C.); (J.A.L.-G.)
| | - Aranzazu Rodríguez-Hernández
- Department of Dermatology, Fundación Instituto Valenciano de Oncología, 46009 Valencia, Spain; (E.M.-S.); (A.R.-H.)
| | - Víctor Traves
- Department of Pathological Anatomy, Fundación Instituto Valenciano de Oncología, 46009 Valencia, Spain;
| | - Joaquín Dopazo
- Clinical Bioinformatics Area, Fundación Progreso y Salud, Hospital Virgen del Rocío, 41013 Sevilla, Spain; (M.P.-C.); (J.D.)
- Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 41013 Sevilla, Spain
- Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocío, 41013 Sevilla, Spain;
- Fundación Progreso y Salud-ELIXIR-es, Hospital Virgen del Rocío, 41013 Sevilla, Spain
| | - Amaya Virós
- Skin Cancer and Aging Lab, Cancer Research UK Manchester Institute, University of Manchester, Manchester SK10 4TG, UK;
| | - Rajiv Kumar
- Division of Functional Genome Analysis, Deutsches Krebsforschüngzentrum, 69120 Heidelberg, Germany;
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska, 142 20 Prague, Czech Republic
- Institute of Medical Biometry and Informatics, University of Heidelberg, 69117 Heidelberg, Germany
| | - Eduardo Nagore
- School of Medicine, Universidad Católica de València San Vicente Mártir, 46001 Valencia, Spain;
- Department of Dermatology, Fundación Instituto Valenciano de Oncología, 46009 Valencia, Spain; (E.M.-S.); (A.R.-H.)
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46
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Jin S, Wang Q, Wu H, Pang D, Xu S. Oncolytic viruses for triple negative breast cancer and beyond. Biomark Res 2021; 9:71. [PMID: 34563270 PMCID: PMC8466906 DOI: 10.1186/s40364-021-00318-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/29/2021] [Indexed: 12/18/2022] Open
Abstract
Biological therapy is considered an alternative treatment capable of eliciting the same effects on tumors as surgery, radiotherapy, and chemotherapy. As a major player in biological therapy, oncolytic viruses (OVs) have attracted great attention and achieved good results. Specifically, the successful application of OVs in head and neck cancer, as well as melanoma, promoted its research in triple negative breast cancer (TNBC). TNBC is a high-risk molecular type of breast cancer, characterized by strong invasion, easy recurrence, and metastasis. Due to the absence of estrogen and progesterone receptors, as well as the absence of overexpression or gene amplification of human epidermal growth factor receptor 2 (HER2), endocrine therapy and anti HER-2 targeted therapy have proven ineffective. Although chemotherapy has shown substantial efficacy in some TNBC patients, the occurrence of drug resistance and poor prognosis have prompted the exploration of new and effective treatment methods. The emerging concept of OVs provides a new platform to treat TNBC. Indeed, several studies have confirmed the therapeutic effects of OVs in TNBC. Numerous studies have also investigated the efficacy of OVs in other malignances, including solid tumor clinical trials, thus further demonstrating the promising application of oncolytic virotherapy for TNBC. The primary focus of the current review is the examination of OV mechanisms underlying their antitumor properties, while also summarizing the ongoing progress in OV research regarding TNBC treatment, as well as the various combinatorial strategies comprising OVs and other therapies. We also briefly introduce specific relevant clinical trials and discuss some of the progress in the research of novel OVs for the treatment of other malignancies, thereby affirming the significant therapeutic potential of OVs for the treatment of TNBC, as well as other cancers.
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Affiliation(s)
- Shengye Jin
- Harbin Medical University, 157 Baojian Road, Harbin, 150086, China.,Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China
| | - Qin Wang
- Sino-Russian Medical Research Cen8ter, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China.,Heilongjiang Academy of Medical Sciences, 157 Baojian Road, Harbin, 150086, China.,Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, 150 Haping Road, Harbin, 1550081, China
| | - Hao Wu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China.,Sino-Russian Medical Research Cen8ter, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China.,Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, 150 Haping Road, Harbin, 1550081, China
| | - Da Pang
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China. .,Sino-Russian Medical Research Cen8ter, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China. .,Heilongjiang Academy of Medical Sciences, 157 Baojian Road, Harbin, 150086, China.
| | - Shouping Xu
- Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China. .,Heilongjiang Academy of Medical Sciences, 157 Baojian Road, Harbin, 150086, China. .,Translational Medicine Research and Cooperation Center of Northern China, Harbin Medical University, 150 Haping Road, Harbin, 1550081, China.
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47
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Xu L, Leng C, Chen L, Dong H, Chen Y, Chen X. Hypothyroidism is a predictive factor of superior antitumour efficacy of programmed death 1 inhibitors in hepatocellular carcinoma. Int J Cancer 2021; 150:472-481. [PMID: 34536292 DOI: 10.1002/ijc.33813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/13/2021] [Accepted: 09/09/2021] [Indexed: 12/19/2022]
Abstract
Programmed death 1 (PD-1) inhibitors are widely used for treatment of hepatocellular carcinoma (HCC). Hypothyroidism is commonly associated with this therapy, although the mechanism underlying this complication and effects on patient prognosis remain unclear. We retrospectively analysed the data of patients with HCC who received anti-PD-1 therapy at Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology between January 2018 and May 2020. Based on thyroid function evaluation, patients were categorised into hypothyroidism group and nonhypothyroidism group. Follow-up was completed on February 28, 2021. The primary endpoint of our study was progression free survival (PFS). The study included 74 patients, and the disease control rate was higher in hypothyroidism group (62.7%, 27/43) than in nonhypothyroidism group (36.4%, 11/31) (P = .020). The PFS was longer in hypothyroidism group (7.44 months) than in nonhypothyroidism group (5.68 months) (P = .006). Additionally, the PFS of patients with hypothyroidism before immunotherapy (6.27 months) was also longer than that in nonhypothyroidism group (5.68 months), although the difference was statistically nonsignificant (P = .527). Cox regression analysis showed that the hazard ratios of hypothyroidism, Child-Pugh grade B at initial admission and serum gamma-glutamyl transferase levels >71 U/L before immunotherapy were 0.404 (95% confidence interval [CI]: 0.207-0.791, P = .008), 2.753 (95%CI: 1.127-6.455, P = .026) and 2.469 (95%CI: 1.155-5.277, P = .020), respectively. Hypothyroidism was associated with prognosis in patients with HCC treated with PD-1 inhibitors, and prognosis was more favourable in patients with hypothyroidism than in those without hypothyroidism. Hypothyroidism and the Child-Pugh grade at initial admission were independently associated with patient prognosis.
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Affiliation(s)
- Lei Xu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chao Leng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lin Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hanhua Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yifa Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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48
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Weingarden AR, Rubin SJS, Gubatan J. Immune checkpoint inhibitor-mediated colitis in gastrointestinal malignancies and inflammatory bowel disease. World J Gastrointest Oncol 2021; 13:772-798. [PMID: 34457186 PMCID: PMC8371513 DOI: 10.4251/wjgo.v13.i8.772] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/09/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
Immune checkpoint inhibitors (ICI) have markedly changed the landscape of cancer therapy. By re-invigorating the immune system against tumors, ICI provide novel therapeutic options for a broad variety of malignancies, including many gastrointestinal (GI) cancers. However, these therapies can also induce autoimmune-like side effects in healthy tissue across the body. One of the most common of these side effects is ICI-mediated colitis and diarrhea (IMC). Here, we review the incidence and risk of IMC in ICI therapy, with a focus on what is known regarding IMC in patients with GI malignancies. We also discuss data available on the use of ICI and risk of IMC in patients with pre-existing inflammatory bowel disease, as these patients may have increased risk of IMC due to their underlying intestinal pathology.
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Affiliation(s)
- Alexa R Weingarden
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Redwood City, CA 94063, United States
| | - Samuel J S Rubin
- Stanford University School of Medicine, Stanford University, Redwood City, CA 94063, United States
| | - John Gubatan
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University, Redwood City, CA 94063, United States
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49
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Mineiro dos Santos Garrett NF, Carvalho da Costa AC, Barros Ferreira E, Damiani G, Diniz dos Reis PE, Inocêncio Vasques C. Prevalence of dermatological toxicities in patients with melanoma undergoing immunotherapy: Systematic review and meta-analysis. PLoS One 2021; 16:e0255716. [PMID: 34358260 PMCID: PMC8345892 DOI: 10.1371/journal.pone.0255716] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 07/22/2021] [Indexed: 12/18/2022] Open
Abstract
Background Checkpoint inhibitors have revolutionized advanced melanoma care; however, their cutaneous side effects have not been definitively elucidated. Objective To identify the prevalence of cutaneous toxicity in patients with melanoma treated with immune checkpoint inhibitors as monotherapy and/or in combination with chemotherapy and/or radiotherapy. Materials and methods We performed a systematic review and meta-analysis, which encompassed both clinical trials and observational studies describing the dermatological toxicities in patients treated with immune checkpoint inhibitors. The protocol was registered in the International Prospective Register of Systematic Review under the number CRD42018091915. The searches were performed using the CINAHL, Cochrane CENTRAL, LILACS, LIVIVO, PubMed, Scopus, and Web of Science databases. The methodological quality of the studies was evaluated with the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data Results A total of 9,802 articles were identified in the databases. The final sample comprised 39 studies. The evaluated drugs were ipilimumab, tremelimumab, pembrolizumab, and nivolumab. The results suggest that the most prevalent side effect was grade 1 and 2 pruritus (24%), followed by grade 1 and 2 rash (21%) and grade 1 and 2 vitiligo (10%). Conclusion The most prevalent side effects in patients treated with checkpoint inhibitors are pruritus, rash, and vitiligo, and they are rated mostly as grades 1 and 2 adverse events. Remarkably, vitiligo is most commonly found in patients treated with PD-1 inhibitors.
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Affiliation(s)
| | | | | | - Giovanni Damiani
- Clinical Dermatology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
- Department of Dermatology, Case Western Reserve University, Cleveland, OH, United States of America
- Department of Drug Sciences, University of Padua, Padua, Italy
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50
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Qin H, Vlaminck B, Owoyemi I, Herrmann SM, Leung N, Markovic SN. Successful Treatment of Pembrolizumab-Induced Severe Capillary Leak Syndrome and Lymphatic Capillary Dysfunction. Mayo Clin Proc Innov Qual Outcomes 2021; 5:670-674. [PMID: 34195558 PMCID: PMC8240169 DOI: 10.1016/j.mayocpiqo.2021.01.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Although capillary leak syndrome has a high mortality rate, its trigger, diagnosis, and treatment remain a challenge to clinicians because of the poor understanding of its mechanism and lack of treatment guidelines. With the extended use of immune checkpoint inhibitors in modern oncology, immune checkpoint inhibitor–associated immune-related adverse events have also expanded. We present a case of pembrolizumab-induced capillary leak syndrome and lymphatic capillary dysfunction in which the patient had an excellent clinical response to a tailored treatment strategy.
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Affiliation(s)
- Haixia Qin
- Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Itunu Owoyemi
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | | | - Nelson Leung
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
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