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Manger I, Schmitt C, Berking C, French LE, Vera-Gonzalez J, Heinzerling L. Association of HLA-A*02:01 type with efficacy and toxicity of immune checkpoint inhibitor therapy in melanoma patients: a retrospective cohort study. BMC Cancer 2025; 25:565. [PMID: 40155873 PMCID: PMC11954185 DOI: 10.1186/s12885-025-13857-y] [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: 07/04/2024] [Accepted: 03/04/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICI) are highly effective but may induce severe or even fatal and unpredictable immune-related adverse events (irAEs). It is unclear whether human leukocyte antigen (HLA) genes contribute to the susceptibility of developing irAEs during ICI therapy. METHODS This multicentre retrospective study investigated the association of irAE and outcome with HLA-A*02:01 status in a cohort of 97 patients with metastatic melanoma undergoing ICI therapy. Organ-specific irAEs and therapy outcome as assessed by response rate, progression-free survival (PFS) and overall survival (OS) were analysed depending on HLA type HLA-A*02:01. For the outcome only patients with cutaneous melanoma were analysed. Chi square test, exact fisher test, Kruskal Wallis test and log rank test were employed for statistical analysis (p ≤ 0.05). RESULTS The cohort included 38 HLA-A*02:01 positive (39.2%) and 59 HLA-A*02:01 negative (60.8%) patients. Data showed no evidence of an association of HLA-A*02:01 with organ-specific irAEs except for a numerical difference in immune-related colitis. Furthermore, response rates of the subgroup of patients with metastatic cutaneous melanoma did not differ between the two cohorts. The median PFS was 5 months and 8 months in HLA-A*02:01 positive and negative patients with cutaneous melanoma, respectively. CONCLUSION HLA-A*02:01 was not associated with specific checkpoint inhibitor-induced organ toxicity in this cohort of HLA-A-typed melanoma patients. Interestingly, in the relatively small subgroup of patients with cutaneous melanoma an earlier progression in HLA-A*02:01 positive patients was observed, however not in the long term. These findings are exploratory due to the limited sample size and require validation in larger, prospective cohorts.
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Affiliation(s)
- Isabel Manger
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Uniklinikum Erlangen, CCC Erlangen-EMN, CCC WERA, Erlangen, Germany
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany
| | - Christina Schmitt
- Department of Dermatology and Allergy, LMU University Hospital, LMU Munich, Munich, Germany
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany
| | - Carola Berking
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Uniklinikum Erlangen, CCC Erlangen-EMN, CCC WERA, Erlangen, Germany
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany
| | - Lars E French
- Department of Dermatology and Allergy, LMU University Hospital, LMU Munich, Munich, Germany
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany
- Dr. Philip Frost, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Julio Vera-Gonzalez
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Uniklinikum Erlangen, CCC Erlangen-EMN, CCC WERA, Erlangen, Germany
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany
| | - Lucie Heinzerling
- Department of Dermatology and Allergy, LMU University Hospital, LMU Munich, Munich, Germany.
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany.
- Department of Dermatology, LMU University Hospital Munich, Frauenlobstr. 9-11, Munich, D-80337, Germany.
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Gallucci G, Larocca M, Navazio A, Turazza FM, Inno A, Canale ML, Oliva S, Besutti G, Tedeschi A, Aschieri D, Russo A, Gori S, Silvestris N, Pinto C, Tarantini L. Atherosclerosis and the Bidirectional Relationship Between Cancer and Cardiovascular Disease: From Bench to Bedside, Part 2 Management. Int J Mol Sci 2025; 26:334. [PMID: 39796190 PMCID: PMC11719480 DOI: 10.3390/ijms26010334] [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: 11/16/2024] [Revised: 12/25/2024] [Accepted: 12/29/2024] [Indexed: 01/13/2025] Open
Abstract
The first part of this review highlighted the evolving landscape of atherosclerosis, noting emerging cardiometabolic risk factors, the growing impact of exposomes, and social determinants of health. The prominent role of atherosclerosis in the bidirectional relationship between cardiovascular disease and cancer was also discussed. In this second part, we examine the complex interplay between multimorbid cardio-oncologic patients, cardiometabolic risk factors, and the harmful environments that lend a "syndemic" nature to these chronic diseases. We summarize management strategies targeting disordered cardiometabolic factors to mitigate cardiovascular disease and explore molecular mechanisms enabling more tailored therapies. Importantly, we emphasize the early interception of atherosclerosis through multifactorial interventions that detect subclinical signs (via biomarkers and imaging) to treat modifiable risk factors and prevent clinical events. A concerted preventive effort-referred to by some as a "preventome"-is essential to reduce the burden of atherosclerosis-driven chronic diseases, shifting from mere chronic disease management to the proactive promotion of "chronic health".
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Affiliation(s)
| | - Mario Larocca
- Provincial Medical Oncology, Department of Oncology and Advanced Technologies, AUSL—IRCCS in Tecnologie Avanzate e Modelli Assistenziali in Oncologia, 42100 Reggio Emilia, Italy; (M.L.); (C.P.)
| | - Alessandro Navazio
- Cardiologia Ospedaliera, Department of Specialized Medicine, AUSL—IRCCS in Tecnologie Avanzate e Modelli Assistenziali in Oncologia, 42100 Reggio Emilia, Italy;
| | | | - Alessandro Inno
- Oncologia Medica, IRCCS Ospedale Sacro Cuore Don Calabria, 37024 Negrar di Valpolicella, Italy; (A.I.)
| | - Maria Laura Canale
- Division of Cardiology, Azienda USL Toscana Nord-Ovest, Versilia Hospital, 55041 Lido di Camaiore, Italy;
| | - Stefano Oliva
- UOSD Cardiologia di Interesse Oncologico IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | - Giulia Besutti
- Radiology Unit, Department of Imaging and Laboratory Medicine, AUSL—IRCCS di Reggio Emilia, 42100 Reggio Emilia, Italy;
- Department of Surgical and Medical Sciences of Children and Adults, University of Modena and Reggio Emilia, 41100 Modena, Italy
| | - Andrea Tedeschi
- Cardiology Unit of Emergency Department, Guglielmo da Saliceto Hospital, 29100 Piacenza, Italy; (A.T.); (D.A.)
| | - Daniela Aschieri
- Cardiology Unit of Emergency Department, Guglielmo da Saliceto Hospital, 29100 Piacenza, Italy; (A.T.); (D.A.)
| | - Antonio Russo
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, 90127 Palermo, Italy;
| | - Stefania Gori
- Oncologia Medica, IRCCS Ospedale Sacro Cuore Don Calabria, 37024 Negrar di Valpolicella, Italy; (A.I.)
| | - Nicola Silvestris
- Medical Oncology Department, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | - Carmine Pinto
- Provincial Medical Oncology, Department of Oncology and Advanced Technologies, AUSL—IRCCS in Tecnologie Avanzate e Modelli Assistenziali in Oncologia, 42100 Reggio Emilia, Italy; (M.L.); (C.P.)
| | - Luigi Tarantini
- Cardiologia Ospedaliera, Department of Specialized Medicine, AUSL—IRCCS in Tecnologie Avanzate e Modelli Assistenziali in Oncologia, 42100 Reggio Emilia, Italy;
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3
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Chen CB, Hung SI, Chang JWC, Yang CK, Ma DHK, Teng YC, Lu CW, Chen WT, Yang HY, Tsai CC, Wang CL, Chiang PH, Wu J, Tsai YW, Lu LY, Lin YYW, Hui RCY, Hsieh FM, Hsu CK, Lee CN, Chen YJ, Chen CC, Cui Y, Hsu HC, Chang YC, Chang CJ, Lin HC, Chang CJ, Lin YJ, Ku CL, Wang CW, Chung WH. Immune checkpoint inhibitor-induced severe epidermal necrolysis mediated by macrophage-derived CXCL10 and abated by TNF blockade. Nat Commun 2024; 15:10733. [PMID: 39737932 DOI: 10.1038/s41467-024-54180-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 11/05/2024] [Indexed: 01/01/2025] Open
Abstract
Immune checkpoint inhibitors (ICI) represent new anticancer agents and have been used worldwide. However, ICI can potentially induce life-threatening severe cutaneous adverse reaction (SCAR), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hindering continuous ICI therapy. We examine 6 cohorts including 25 ICI-induced SJS/TEN patients and conduct single-cell RNA sequencing (scRNA-seq) analysis, which shows overexpression of macrophage-derived CXCL10 that recruits CXCR3+ cytotoxic T lymphocytes (CTL) in blister cells from ICI-SJS/TEN skin lesions. ScRNA expression profiles and ex vivo blocking studies further identify TNF signaling as a pathway responsible for macrophage-derived CXCL10 and CTL activation. Based on the trajectory analysis, ICI-activated T cells from whole blood are proposed to serve as the initial cells involved in inflammation, that lead to monocytes differentiating into macrophages and increasing their susceptibility to migrate to the lesion sites. Compared with systemic corticosteroids treatment, ICI-induced SJS/TEN patients treated with biologic TNF blockade showed a significantly rapid recovery and no recurrence of SCAR with continuous ICI therapy. Our findings identify that macrophage-eliciting CTL contribute to the pathogenesis of ICI-induced epidermal necrolysis and provide potential therapeutic targets for the management and prevention of SCAR induced by ICI therapy.
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Affiliation(s)
- Chun-Bing Chen
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Chang Gung Immunology Consortium, Chang Gung University, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
- Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
- Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
- Xiamen Chang Gung Allergology Consortium, Xiamen Chang Gung Hospital, Xiamen, China
| | - Shuen-Iu Hung
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Institute of Pharmacology, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
| | - John Wen-Cheng Chang
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Hematology-Oncology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Chan-Keng Yang
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Division of Hematology-Oncology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - David Hui-Kang Ma
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Limbal Stem Cell Laboratory, Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Yu-Chuan Teng
- Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Chun-Wei Lu
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ti Chen
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Hsiao-Yin Yang
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Cheng-Chang Tsai
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Chih Liang Wang
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Pin-Hsuan Chiang
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Dermatology, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan
| | - Jennifer Wu
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Ya-Wen Tsai
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Lai-Ying Lu
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Yang Yu-Wei Lin
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Rosaline Chung-Yee Hui
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | | | - Chao-Kai Hsu
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chaw-Ning Lee
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Ju Chen
- Institute of Clinical Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
- Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chih-Chiang Chen
- Institute of Clinical Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
- Department of Dermatology, Taipei Veterans General Hospital, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yilei Cui
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Hung-Chih Hsu
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Division of Hematology-Oncology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Ya-Ching Chang
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chih-Jung Chang
- Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China
- Xiamen Chang Gung Allergology Consortium, Xiamen Chang Gung Hospital, Xiamen, China
- Medical Research Center, Xiamen Chang Gung Hospital, Xiamen, China
- School of Medicine, Huaqiao University, Quanzhou, China
| | - Ho-Chen Lin
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Chee Jen Chang
- Research Services Center for Health Information, Chang Gung University, Taoyuan, Taiwan
- Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Jr Lin
- Research Services Center for Health Information, Chang Gung University, Taoyuan, Taiwan
- Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Lung Ku
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
- Chang Gung Immunology Consortium, Chang Gung University, Taoyuan, Taiwan.
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Laboratory of Human Immunology and Infectious Disease, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
- Center for Molecular and Clinical and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Division of Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
| | - Chuang-Wei Wang
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
- Chang Gung Immunology Consortium, Chang Gung University, Taoyuan, Taiwan.
- Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China.
- Xiamen Chang Gung Allergology Consortium, Xiamen Chang Gung Hospital, Xiamen, China.
- Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Wen-Hung Chung
- Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
- Department of Dermatology, Chang Gung Memorial Hospital, Keelung Branch, Keelung, Taiwan.
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
- Chang Gung Immunology Consortium, Chang Gung University, Taoyuan, Taiwan.
- College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan.
- Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan.
- Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, China.
- Xiamen Chang Gung Allergology Consortium, Xiamen Chang Gung Hospital, Xiamen, China.
- Department of Dermatology, Beijing Tsinghua Chang Gung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
- Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Takagi K, Sukhbaatar A, Inaba Y, Mori S, Kodama T. A combination of lymphatic drug delivery of anti-CTLA-4 antibody and local radiotherapy for solid-tumor treatment. Cancer Sci 2024; 115:4021-4033. [PMID: 39380185 PMCID: PMC11611777 DOI: 10.1111/cas.16369] [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: 03/13/2024] [Revised: 09/23/2024] [Accepted: 09/25/2024] [Indexed: 10/10/2024] Open
Abstract
The combination of radiotherapy and immunotherapy is a promising approach that has been shown in clinical trials to improve significantly survival and response rates compared with monotherapy against solid tumor. Since anti-CTLA-4 antibodies block immunosuppressive signals mainly in the lymph nodes (LNs), efficient drug delivery to the lymphatic system is desirable. However, the immune checkpoint inhibitors, especially anti-CTLA-4 are currently administered intravenously (i.v.), resulting in limited efficacy in controlling solid tumor and inhibiting metastases, and the method of administration has not been optimized. Here, we show that a combination of local radiotherapy and administration of anti-CTLA-4 antibodies using a lymphatic drug delivery system (LDDS) suppresses solid tumor and metastases. We compared the efficacy of LDDS-based immunotherapy or radioimmunotherapy with i.v. administration in a solid-tumor model created by subcutaneous inoculation into LN-swollen mice with osteosarcoma cells. Tumor-bearing mice were divided into various groups (no treatment, immunotherapy [i.v. or LDDS], radiotherapy, and radioimmunotherapy [i.v. or LDDS]) and were observed for 28 days. Immunotherapy was administered with a cumulative dose of 10 mg/kg of anti-CTLA-4 monoclonal antibody, and radiotherapy was administered with a cumulative 8 Gy of fractionated X-ray irradiation. For immunotherapy alone, LDDS provided slight tumor growth inhibition but did not inhibit distant metastasis. For radioimmunotherapy, however, tumor growth was delayed and distant metastasis was suppressed compared with radiotherapy alone. In particular, the LDDS group achieved a high tumor-suppressive effect with T cell-mediated immune activity, indicating the efficacy of LDDS in radioimmunotherapy.
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Affiliation(s)
- Koki Takagi
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical EngineeringTohoku UniversitySendaiMiyagiJapan
| | - Ariunbuyan Sukhbaatar
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical EngineeringTohoku UniversitySendaiMiyagiJapan
- Division of Oral and Maxillofacial Oncology and Surgical Sciences, Graduate School of DentistryTohoku UniversitySendaiMiyagiJapan
- Biomedical Engineering Cancer Research Center, Graduate School of Biomedical EngineeringTohoku UniversitySendaiMiyagiJapan
| | - Yohei Inaba
- Department of Radiological TechnologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
- Department of Radiation Disaster MedicineInternational Research Institute of Disaster Science, Tohoku UniversitySendaiMiyagiJapan
| | - Shiro Mori
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical EngineeringTohoku UniversitySendaiMiyagiJapan
- Division of Oral and Maxillofacial Oncology and Surgical Sciences, Graduate School of DentistryTohoku UniversitySendaiMiyagiJapan
- Biomedical Engineering Cancer Research Center, Graduate School of Biomedical EngineeringTohoku UniversitySendaiMiyagiJapan
| | - Tetsuya Kodama
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical EngineeringTohoku UniversitySendaiMiyagiJapan
- Biomedical Engineering Cancer Research Center, Graduate School of Biomedical EngineeringTohoku UniversitySendaiMiyagiJapan
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Beckmann M, Schlüter J, Erdmann M, Kramer R, Cunningham S, Hackstein H, Zimmermann R, Heinzerling L. Interdependence of coagulation with immunotherapy and BRAF/MEK inhibitor therapy: results from a prospective study. Cancer Immunol Immunother 2024; 74:5. [PMID: 39487855 PMCID: PMC11531462 DOI: 10.1007/s00262-024-03850-y] [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: 04/14/2024] [Accepted: 09/27/2024] [Indexed: 11/04/2024]
Abstract
Immune checkpoint inhibitor (ICI) therapies effectively treat a broadening spectrum of cancer entities but induce various immune-related side effects (irAEs). Recent reports suggest a correlation between ICI-induced systemic inflammation and thromboembolic events as well as an increased effectiveness by coadministration of anticoagulants. With cancer patients having a higher risk of thrombotic events per se, it is crucial to dissect and characterize the mechanisms that cause pro-coagulative effects induced by systemic tumor therapies and their potential interplay with anti-tumor response. A total of 31 patients with advanced skin cancer treated with either ICIs (n = 24) or BRAF/MEK inhibitors (n = 7) were longitudinally assessed for blood and coagulation parameters before as well as 7, 20 and 40 days after initiation of systemic tumor therapy. Changes were analyzed and compared between both groups. In addition, the influence of coagulation parameters on progression-free, recurrence-free and overall survival was investigated. The ICI cohort presented significantly increased factor VIII activity after one week of therapy (p 0.0225); while, protein S activity was reduced during the whole observation period. Additionally, von Willebrand factor activity and tissue factor concentrations increased under immunotherapy. Similar changes occurred under BRAF/MEK inhibitor therapy (BRAF/MEKi). Increased baseline levels of von Willebrand factor antigen and factor VIII:C before the start of ICI therapy correlated with a significantly higher risk of recurrence for patients receiving adjuvant immunotherapy. The findings suggest the induction of a pro-coagulant state under ICI and BRAF/MEKi and a role of coagulation parameters in the efficacy of ICI therapies.
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Affiliation(s)
- Malte Beckmann
- Department of Dermatology, Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), University Hospital Erlangen, Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany
| | - Julian Schlüter
- Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany
| | - Michael Erdmann
- Department of Dermatology, Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), University Hospital Erlangen, Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany
| | - Rafaela Kramer
- Department of Dermatology, Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), University Hospital Erlangen, Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany
| | - Sarah Cunningham
- Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany
| | - Holger Hackstein
- Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany
| | - Robert Zimmermann
- Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany
| | - Lucie Heinzerling
- Department of Dermatology, Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), University Hospital Erlangen, Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany.
- Department of Dermatology and Allergology, LMU University Hospital Munich, Ludwig-Maximilian University, Frauenlobstraße 9 - 11, 80337, Munich, Germany.
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Xue D, Li N, Yang J, Men K, Li L, Jiang H, Zhao X, Zhang S. Sarcopenia predicts immune-related adverse events due to anti-PD-1/PD-L1 therapy in patients with advanced lung cancer. Front Oncol 2024; 14:1450020. [PMID: 39376979 PMCID: PMC11456396 DOI: 10.3389/fonc.2024.1450020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 09/02/2024] [Indexed: 10/09/2024] Open
Abstract
Introduction Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a number of patients with advanced cancer, and while this has resulted in increased survival times, it has also led to the emergence of novel immune-related adverse events (irAEs). In individuals with advanced cancer, sarcopenia is a significant symptom of cachexia and is linked to poor nutritional status and increased mortality. The present study aimed to evaluate sarcopenia and other risk variables that can affect the emergence of irAEs in patients with lung cancer. Methods A single-center retrospective analysis of 129 patients with advanced lung cancer treated with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) checkpoint inhibitors was conducted from August 2020 to August 2022. Data on baseline characteristics and adverse events of participants were collected. Computed tomography was used to determine the skeletal muscle index at the third lumbar vertebra (L3-SMI) and whether sarcopenia is present. Results The median age of all participants was 60 years old (range, 52-66 years), with men accounting for 68.9% of the total patient cohort. The present study showed that 44 (34%) participants presented with any degree of irAEs, and 79 (61.2%) patients presented with sarcopenia. There were no statistically significant differences in baseline characteristics, such as age and sex, between patients who presented with irAEs and those without irAEs. Using logistic regression analysis, individuals with sarcopenia were 2.635-times more likely to experience any grade of irAEs than those without sarcopenia. Discussion irAEs are prevalent side effects of PD-1/PD-L1 inhibitor therapy for patients with cancer. By diagnosing and treating sarcopenia early, it is possible to lower the potential risk of irAEs in patients with advanced cancer. Furthermore, sarcopenia can be utilized as a predictor of irAEs.
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Affiliation(s)
| | | | | | | | | | | | | | - Shuai Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
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Nakazawa N, Sohda M, Hosoi N, Watanabe T, Kumakura Y, Yamashita T, Tanaka N, Saito K, Kimura A, Kasuga K, Nakazato K, Yoshinari D, Shimizu H, Ubukata Y, Hosaka H, Sano A, Sakai M, Ogawa H, Shirabe K, Saeki H. Identification of Biomarkers for Assessing Treatment Efficacy of Chemotherapy plus Nivolumab as the First Line in Patients with Unresectable Advanced or Recurrent Gastric Cancer: A Multicenter Study. Oncology 2024; 103:201-208. [PMID: 39265540 DOI: 10.1159/000540841] [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: 04/22/2024] [Accepted: 07/30/2024] [Indexed: 09/14/2024]
Abstract
INTRODUCTION In this study, we aimed to identify biomarkers for predicting treatment outcomes and efficacy of chemotherapy plus nivolumab, as well as predict immune-related adverse events (irAEs) characteristics of immune checkpoint inhibitors. METHODS This multicenter study included 104 patients who received chemotherapy plus nivolumab as the primary treatment for unresectable advanced recurrent gastric cancer. Blood test results were collected before the start and after two courses of treatment. The neutrophil-lymphocyte ratio, prognostic nutritional index, and lactate dehydrogenase/albumin ratio (LAR) were examined after treatment in each case to determine changes compared to values before the start of treatment. RESULTS A total of 57 (54.8%) patients experienced a complete or partial response. The LAR of the stable disease/progressive disease group significantly increased (p = 0.018). An examination of the presence of grade ≥3 irAEs and changes in related factors showed that the LAR of all patients increased. CONCLUSION The LAR was correlated with the best therapeutic response; therefore, it may be a potential biomarker of treatment outcomes and efficacy.
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Affiliation(s)
- Nobuhiro Nakazawa
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Makoto Sohda
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Nobuhiro Hosoi
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Takayoshi Watanabe
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yuji Kumakura
- Department of Surgery, Tonechuo Hospital, Numata, Japan
| | - Toshiki Yamashita
- Department of Surgery, Subaru Health Insurance Society Ota Memorial Hospital, Ota, Japan
| | - Naritaka Tanaka
- Department of Surgery, Japanese Red Cross Haramachi Hospital, Agatsumagun, Japan
| | - Kana Saito
- Department of Surgery, Japan Community Healthcare Organization, Gunma Central Hospital, Maebashi, Japan
| | - Akiharu Kimura
- Department of Surgery, Kiryu Kosei General Hospital, Kiryu, Japan
| | - Kengo Kasuga
- Department of Gastroenterology, Isesaki Municipal Hospital, Isesaki, Japan
| | - Kenji Nakazato
- Department of Surgery, Fujioka General Hospital, Fujioka, Japan
| | - Daisuke Yoshinari
- Department of Surgery, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan
| | - Hisashi Shimizu
- Department of Surgery, Japanese Red Cross Maebashi Hospital, Maebashi, Japan
| | - Yasunari Ubukata
- Department of Surgery, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Hisashi Hosaka
- Department of Gastroenterology, Gunma Prefectural Cancer Center, Ota, Japan
| | - Akihiko Sano
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Makoto Sakai
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hiroomi Ogawa
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Ken Shirabe
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hiroshi Saeki
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan
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O'Hare M, Guidon AC. Peripheral nervous system immune-related adverse events due to checkpoint inhibition. Nat Rev Neurol 2024; 20:509-525. [PMID: 39122934 DOI: 10.1038/s41582-024-01001-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2024] [Indexed: 08/12/2024]
Abstract
Immune checkpoint inhibitors have revolutionized cancer therapy and are increasingly used to treat a wide range of oncological conditions, with dramatic benefits for many patients. Unfortunately, the resulting increase in T cell effector function often results in immune-related adverse events (irAEs), which can involve any organ system, including the central nervous system (CNS) and peripheral nervous system (PNS). Neurological irAEs involve the PNS in two-thirds of affected patients. Muscle involvement (immune-related myopathy) is the most common PNS irAE and can be associated with neuromuscular junction involvement. Immune-related peripheral neuropathy most commonly takes the form of polyradiculoneuropathy or cranial neuropathies. Immune-related myopathy (with or without neuromuscular junction involvement) often occurs along with immune-related myocarditis, and this overlap syndrome is associated with substantially increased mortality. This Review focuses on PNS adverse events associated with immune checkpoint inhibition. Underlying pathophysiological mechanisms are discussed, including antigen homology between self and tumour, epitope spreading and activation of pre-existing autoreactive T cells. An overview of current approaches to clinical management is provided, including cytokine-directed therapies that aim to decouple anticancer immunity from autoimmunity and emerging treatments for patients with severe (life-threatening) presentations.
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Affiliation(s)
- Meabh O'Hare
- Brigham and Women's Hospital, Division of Neuromuscular Medicine, Department of Neurology, Boston, MA, USA.
- Massachusetts General Hospital, Division of Neuromuscular Medicine, Department of Neurology, Boston, MA, USA.
| | - Amanda C Guidon
- Massachusetts General Hospital, Division of Neuromuscular Medicine, Department of Neurology, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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Guo AJ, Deng QY, Dong P, Zhou L, Shi L. Biomarkers associated with immune-related adverse events induced by immune checkpoint inhibitors. World J Clin Oncol 2024; 15:1002-1020. [PMID: 39193157 PMCID: PMC11346067 DOI: 10.5306/wjco.v15.i8.1002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 05/13/2024] [Accepted: 06/21/2024] [Indexed: 08/16/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) constitute a pivotal class of immunotherapeutic drugs in cancer treatment. However, their widespread clinical application has led to a notable surge in immune-related adverse events (irAEs), significantly affecting the efficacy and survival rates of patients undergoing ICI therapy. While conventional hematological and imaging tests are adept at detecting organ-specific toxicities, distinguishing adverse reactions from those induced by viruses, bacteria, or immune diseases remains a formidable challenge. Consequently, there exists an urgent imperative for reliable biomarkers capable of accurately predicting or diagnosing irAEs. Thus, a thorough review of existing studies on irAEs biomarkers is indispensable. Our review commences by providing a succinct overview of major irAEs, followed by a comprehensive summary of irAEs biomarkers across various dimensions. Furthermore, we delve into innovative methodologies such as machine learning, single-cell RNA sequencing, multiomics analysis, and gut microbiota profiling to identify novel, robust biomarkers that can facilitate precise irAEs diagnosis or prediction. Lastly, this review furnishes a concise exposition of irAEs mechanisms to augment understanding of irAEs prediction, diagnosis, and treatment strategies.
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Affiliation(s)
- An-Jie Guo
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Qing-Yuan Deng
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Pan Dong
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Lian Zhou
- Head and Neck Cancer Center, Chongqing University Cancer Hospital, Chongqing 400000, China
| | - Lei Shi
- School of Life Sciences, Chongqing University, Chongqing 400044, China
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Wang Y, Ertl C, Schmitt C, Hammann L, Kramer R, Grabmaier U, Schöberl F, Anz D, Piseddu I, Pesch G, Vera J, Froehlich W, Weckbach L, Tomsitz D, Loquai C, Zimmer L, Mangana J, Dummer R, Gutzmer R, Klespe KC, Stege H, Meiss F, Thoms KM, Terheyden P, Bröckelmann PJ, Johnson DB, French LE, Heinzerling L. Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity. Front Cardiovasc Med 2024; 11:1408586. [PMID: 38915743 PMCID: PMC11194425 DOI: 10.3389/fcvm.2024.1408586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/14/2024] [Indexed: 06/26/2024] Open
Abstract
Background Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management. Methods Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry. Results A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis. Conclusion Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.
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Affiliation(s)
- Ying Wang
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - Carolin Ertl
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
- SERIO Registry, Munich, Germany
| | - Christina Schmitt
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - Linda Hammann
- Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Rafaela Kramer
- Department of Dermatology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen (UKER), Deutsches Zentrum Immuntherapie (DZI) and Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nürnberg (CCC-ER-EMN), Erlangen, Germany
| | - Ulrich Grabmaier
- Department of Medicine I, LMU University Hospital, LMU Munich, Munich, Germany
| | - Florian Schöberl
- Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany
- German Center for Vertigo and Balance Disorders (DSGZ), LMU University Hospital, LMU Munich, Munich, Germany
| | - David Anz
- Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
- Department of Medicine II, LMU University Hospital, LMU Munich, Munich, Germany
| | - Ignazio Piseddu
- Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
- Department of Medicine II, LMU University Hospital, LMU Munich, Munich, Germany
| | - Giulia Pesch
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - Julio Vera
- Department of Dermatology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen (UKER), Deutsches Zentrum Immuntherapie (DZI) and Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nürnberg (CCC-ER-EMN), Erlangen, Germany
| | - Waltraud Froehlich
- Division of Clinical Pharmacology, Klinikum der Universität München, Munich, Germany
| | - Ludwig Weckbach
- Department of Medicine I, LMU University Hospital, LMU Munich, Munich, Germany
| | - Dirk Tomsitz
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - Carmen Loquai
- Department of Dermatology, Klinikum Bremen-Ost, Gesundheit Nord gGmbH, Bremen, Germany
| | - Lisa Zimmer
- Department of Dermatology, University Hospital Essen & German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, & National Center for Tumor Diseases (NCT)-West, Campus Essen, & Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany
| | - Johanna Mangana
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Reinhard Dummer
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Ralf Gutzmer
- Department of Dermatology, Johannes Wesling Medical Center, Mühlenkreiskliniken (MKK), Ruhr University Bochum, Minden, Germany
| | - Kai-Christian Klespe
- Skin Cancer Center Hannover, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany
| | - Henner Stege
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Frank Meiss
- Faculty of Medicine, Department of Dermatology, Medical Center—University of Freiburg, Freiburg, Germany
| | - Kai-Martin Thoms
- Department of Dermatology, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany
| | | | - Paul J. Bröckelmann
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
| | - Douglas B. Johnson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Lars E. French
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
- Dr. Philip Frost, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Lucie Heinzerling
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
- SERIO Registry, Munich, Germany
- Department of Dermatology, Friedrich-Alexander University Erlangen-Nürnberg (FAU) and University Hospital Erlangen (UKER), Deutsches Zentrum Immuntherapie (DZI) and Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nürnberg (CCC-ER-EMN), Erlangen, Germany
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11
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Yeung SCJ, Qdaisat A, Bischof JJ, Caterino JM, Kyriacou DN, Coyne Md C. A case series of adrenal insufficiency (likely due to hypophysitis) in cancer patients treated with immune checkpoint inhibitors. Am J Emerg Med 2024; 80:227.e1-227.e5. [PMID: 38705758 DOI: 10.1016/j.ajem.2024.04.046] [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: 12/05/2023] [Revised: 03/24/2024] [Accepted: 04/26/2024] [Indexed: 05/07/2024] Open
Abstract
The number of approved immune checkpoint inhibitors (ICIs) and their indications have significantly increased over the past decade. Immune-related adverse effects (irAEs) of ICIs vary widely in presentation and symptoms and can present diagnostic challenges to emergency department (ED) physicians. Moreover, when ICIs are combined with radiotherapy, cytotoxic chemotherapy, or targeted therapy, the attribution of signs and symptoms to an immune-related cause is even more difficult. Here, we report a series of 5 ED cases of adrenal insufficiency in ICI-treated cancer patients. All 5 patients presented with severe fatigue and nausea. Four patients definitely had and one patient possibly had central adrenal insufficiency, and 4 patients had undetectable serum cortisol levels. The majority of the patients had nonspecific symptoms that were not recognized at their first ED presentation. These cases illustrate the need for a heightened level of suspicion for adrenal insufficiency in ICI-treated cancer patients with hypotension, nausea and/or vomiting, abdominal pain, fatigue, or hypoglycemia. As ICI use increases, irAE-associated oncologic emergencies will become more prevalent. Thus, ED physicians must update their knowledge regarding the diagnosis and management of irAEs and routinely inquire about the specific antineoplastic therapies that their ED patients with cancer are receiving. A random cortisol level (results readily available in most EDs) with interpretation taking the circadian rhythm and the current level of physiological stress into consideration can inform the differential diagnosis and whether further investigation of this potential irAE is warranted.
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Affiliation(s)
- Sai-Ching Jim Yeung
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
| | - Aiham Qdaisat
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jason J Bischof
- Department of Emergency Medicine, Ohio State University, Columbus, OH, United States
| | - Jeffrey M Caterino
- Department of Emergency Medicine, Ohio State University, Columbus, OH, United States
| | - Demetrios N Kyriacou
- Department of Emergency Medicine, Northwestern University, Chicago, IL, United States
| | - Christopher Coyne Md
- Department of Emergency Medicine, University of California San Diego, San Diego, CA, United States
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Devitt L, Westphal D, Pieger K, Schneider N, Bosserhoff AK, Kuphal S. NRN1 interacts with Notch to increase oncogenic STAT3 signaling in melanoma. Cell Commun Signal 2024; 22:256. [PMID: 38705997 PMCID: PMC11071257 DOI: 10.1186/s12964-024-01632-8] [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: 02/29/2024] [Accepted: 04/24/2024] [Indexed: 05/07/2024] Open
Abstract
BACKGROUND Melanoma is a highly heterogeneous cancer, in which frequent changes in activation of signaling pathways lead to a high adaptability to ever changing tumor microenvironments. The elucidation of cancer specific signaling pathways is of great importance, as demonstrated by the inhibitor of the common BrafV600E mutation PLX4032 in melanoma treatment. We therefore investigated signaling pathways that were influenced by neurotrophin NRN1, which has been shown to be upregulated in melanoma. METHODS Using a cell culture model system with an NRN1 overexpression, we investigated the influence of NRN1 on melanoma cells' functionality and signaling. We employed real time cell analysis and spheroid formation assays, while for investigation of molecular mechanisms we used a kinase phosphorylation kit as well as promotor activity analysis followed by mRNA and protein analysis. RESULTS We revealed that NRN1 interacts directly with the cleaved intracellular domain (NICD) of Notch1 and Notch3, causing a potential retention of NICD in the cytoplasm and thereby reducing the expression of its direct downstream target Hes1. This leads to decreased sequestration of JAK and STAT3 in a Hes1-driven phosphorylation complex. Consequently, our data shows less phosphorylation of STAT3 while presenting an accumulation of total protein levels of STAT3 in association with NRN1 overexpression. The potential of the STAT3 signaling pathway to act in both a tumor suppressive and oncogenic manner led us to investigate specific downstream targets - namely Vegf A, Mdr1, cMet - which were found to be upregulated under oncogenic levels of NRN1. CONCLUSIONS In summary, we were able to show that NRN1 links oncogenic signaling events between Notch and STAT3 in melanoma. We also suggest that in future research more attention should be payed to cellular regulation of signaling molecules outside of the classically known phosphorylation events.
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Affiliation(s)
- Lucia Devitt
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Dana Westphal
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT) Dresden, a partnership between German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Katharina Pieger
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Nadja Schneider
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Anja Katrin Bosserhoff
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany
| | - Silke Kuphal
- Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Fahrstrasse 17, Erlangen, 91054, Germany.
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13
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Ruf T, Kramer R, Forschner A, Leiter U, Meier F, Reinhardt L, Dücker P, Ertl C, Tomsitz D, Tietze JK, Gutzmer R, Dabrowski E, Zimmer L, Gesierich A, Zierold S, French LE, Eigentler T, Amaral T, Heinzerling L. Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors. Eur J Cancer 2024; 203:114028. [PMID: 38652976 DOI: 10.1016/j.ejca.2024.114028] [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: 01/10/2024] [Revised: 03/03/2024] [Accepted: 03/12/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking. METHODS The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies. RESULTS From a total of 1330 cases, 217 patients (16.3%) received 249 second-line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only. CONCLUSION Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed.
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Affiliation(s)
- Theresa Ruf
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany; SERIO registry
| | - Rafaela Kramer
- Department of Dermatology, University Clinic Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; SERIO registry
| | - Andrea Forschner
- Department of Dermatology, Eberhard-Karls-University of Tübingen, Tübingen, Germany
| | - Ulrike Leiter
- Department of Dermatology, Eberhard-Karls-University of Tübingen, Tübingen, Germany
| | - Friedegund Meier
- Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Lydia Reinhardt
- Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Germany
| | - Pia Dücker
- Department of Dermatology, Hospital Dortmund, Dortmund, Germany
| | - Carolin Ertl
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany; SERIO registry
| | - Dirk Tomsitz
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany
| | - Julia K Tietze
- Clinic for Dermatology and Venerology, University Medical Center Rostock, Rostock, Germany
| | - Ralf Gutzmer
- Department of Dermatology, Johannes Wesling Medical Center, Ruhr-University Bochum, Minden, Germany
| | | | - Lisa Zimmer
- Department of Dermatology, Essen University Hospital, West German Cancer Center, University of Duisburg-Essen and the German Cancer Consortium (DKTK), Partner site Essen/Düsseldorf, Germany
| | - Anja Gesierich
- Department of Dermatology, University Hospital Würzburg, Germany
| | - Sarah Zierold
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany; SERIO registry
| | - Lars E French
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany; Dr. Philip Frost Department of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Thomas Eigentler
- Department of Dermatology, Charité University Medicine Berlin, Berlin, Germany
| | - Teresa Amaral
- Department of Dermatology, Eberhard-Karls-University of Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180), Tübingen, Germany
| | - Lucie Heinzerling
- Department of Dermatology and Allergology, University Hospital, LMU Munich, Munich, Germany; Department of Dermatology, University Clinic Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; SERIO registry.
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14
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Liang Y, Maeda O, Ando Y. Biomarkers for immune-related adverse events in cancer patients treated with immune checkpoint inhibitors. Jpn J Clin Oncol 2024; 54:365-375. [PMID: 38183211 PMCID: PMC11771318 DOI: 10.1093/jjco/hyad184] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 12/12/2023] [Indexed: 01/07/2024] Open
Abstract
Although immune checkpoint inhibitors have greatly improved cancer therapy, they also cause immune-related adverse events, including a wide range of inflammatory side effects resulting from excessive immune activation. Types of immune-related adverse events are diverse and can occur in almost any organ, with different frequencies and severities. Furthermore, immune-related adverse events may occur within the first few weeks after treatment or even several months after treatment discontinuation. Predictive biomarkers include blood cell counts and cell surface markers, serum proteins, autoantibodies, cytokines/chemokines, germline genetic variations and gene expression profiles, human leukocyte antigen genotype, microRNAs and the gut microbiome. Given the inconsistencies in research results and limited practical utility, there is to date no established biomarker that can be used in routine clinical practice, and additional investigations are essential to demonstrate efficacy and subsequently facilitate integration into routine clinical use.
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Affiliation(s)
- Yao Liang
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Osamu Maeda
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Yuichi Ando
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan
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15
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Kim SY, Kim DK, Choi SY, Chung C. Comparative analysis of immunotherapy responses in small cell lung cancer patients with dermatomyositis. Thorac Cancer 2024; 15:672-677. [PMID: 38352989 DOI: 10.1111/1759-7714.15238] [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: 12/11/2023] [Accepted: 01/20/2024] [Indexed: 03/13/2024] Open
Abstract
Cancer-associated dermatomyositis (CAD), a paraneoplastic syndrome characterized by dermatomyositis (DM), frequently presents in association with small cell lung cancer (SCLC). Although the advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, their efficacy and safety in patients with concurrent autoimmune diseases (AD) and malignancies remains uncertain. Several studies have suggested the safe administration of ICIs in patients with AD, indicating that successful cancer therapy can alleviate CAD symptoms. Conversely, other studies have raised concerns about the potential for ICIs to exacerbate AD flares or immune-related adverse events (irAEs). A comparative analysis of two cases from our institution emphasizes the variability in ICI responses among SCLC patients with CAD. One patient, previously reported as a case study, exhibited significant clinical improvement in DM symptoms after ICI administration, whereas the other developed severe exfoliative skin changes and experienced an unfavorable prognosis. This variability emphasizes the need for careful patient selection and close monitoring during ICI treatment. We hypothesized that overweight or obese individuals and those with severe initial skin lesions and elevated lactate dehydrogenase levels are more susceptible to developing irAEs following ICI therapy. Therefore, caution is advised when considering immunotherapy in these patients.
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Affiliation(s)
- So-Yun Kim
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Duk Ki Kim
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Song-Yi Choi
- Department of pathology, College of Medicine, Chungnam National University, Daejeon, South Korea
| | - Chaeuk Chung
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea
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16
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Schmitt C, Hoefsmit EP, Fangmeier T, Kramer N, Kabakci C, Vera González J, Versluis JM, Compter A, Harrer T, Mijočević H, Schubert S, Hundsberger T, Menzies AM, Scolyer RA, Long GV, French LE, Blank CU, Heinzerling LM. Immune checkpoint inhibitor-induced neurotoxicity is not associated with seroprevalence of neurotropic infections. Cancer Immunol Immunother 2023; 72:3475-3489. [PMID: 37606856 PMCID: PMC10576679 DOI: 10.1007/s00262-023-03498-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/07/2023] [Indexed: 08/23/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1-5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs. METHODS Neurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy. RESULTS The association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity. CONCLUSION Previous viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.
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Affiliation(s)
- C Schmitt
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - E P Hoefsmit
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - T Fangmeier
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - N Kramer
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - C Kabakci
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - J Vera González
- Department of Dermatology, Uniklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - J M Versluis
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - A Compter
- Department of Neuro-Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - T Harrer
- Department of Internal Medicine 3, Infectious Diseases and Immunodeficiency Section, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - H Mijočević
- Max Von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - S Schubert
- Max Von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - T Hundsberger
- Departments of Neurology and Medical Oncology/Haematology, Cantonal Hospital, St. Gallen, Switzerland
| | - A M Menzies
- Melanoma Institute of Australia, The University of Sydney, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia
| | - R A Scolyer
- Melanoma Institute of Australia, The University of Sydney, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia
| | - G V Long
- Melanoma Institute of Australia, The University of Sydney, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - L E French
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
- Dr. Philip Frost, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - C U Blank
- Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
| | - L M Heinzerling
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany.
- Department of Dermatology, Uniklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
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17
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Pašalić D, Nikuševa-Martić T, Sekovanić A, Kaštelan S. Genetic and Epigenetic Features of Uveal Melanoma-An Overview and Clinical Implications. Int J Mol Sci 2023; 24:12807. [PMID: 37628989 PMCID: PMC10454135 DOI: 10.3390/ijms241612807] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/09/2023] [Accepted: 08/13/2023] [Indexed: 08/27/2023] Open
Abstract
Uveal melanoma (UM) is rare, but it is the most common primary intraocular malignancy among adults. This review represents the molecular, genetic, and immunobiological mechanisms involved in UM carcinogenesis and progression, as well as data about the association of chromosomal changes, genetic mutations, selective proteins, and biochemical biomarkers with the clinical implications of UM. Genetic analysis has the potential to identify patients with a high risk of UM metastasis, enabling management that is more effective and allowing for the follow-up of patients. Advancements in molecular characterization of UM offer opportunities to develop targeted therapeutic strategies by focusing on relevant signaling pathways. Changes in miRNA expression could be useful in the diagnosis and prognosis of UM, due to unique miRNA profiles in melanoma cells or tissue and its association with metastasis. Although liver function tests do not provide enough data on the prognosis of UM, due to the high frequency of liver metastasis, liver function tests (LFTs) might be useful indicators; however, the absence of rising LFT values cannot lead to the exclusion of liver metastases. Molecular analysis of tumor tissue will allow us to identify patients with the added benefit of new therapeutic agents and provide a better insight into melanoma pathogenesis and its biological behavior.
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Affiliation(s)
- Daria Pašalić
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Tamara Nikuševa-Martić
- Department of Biology and Genetics, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ankica Sekovanić
- Institute for Medical Research and Occupational Health, 10000 Zagreb, Croatia;
| | - Snježana Kaštelan
- Department of Ophthalmology and Optometry, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Department of Ophthalmology, Clinical Hospital Dubrava, 10000 Zagreb, Croatia
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18
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Lepper A, Bitsch R, Özbay Kurt FG, Arkhypov I, Lasser S, Utikal J, Umansky V. Melanoma patients with immune-related adverse events after immune checkpoint inhibitors are characterized by a distinct immunological phenotype of circulating T cells and M-MDSCs. Oncoimmunology 2023; 12:2247303. [PMID: 37593676 PMCID: PMC10431726 DOI: 10.1080/2162402x.2023.2247303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 08/09/2023] [Accepted: 08/09/2023] [Indexed: 08/19/2023] Open
Abstract
Treatment with immune checkpoint inhibitors (ICIs) has improved the prognosis of melanoma patients. However, ICIs can cause an overactivation of the immune system followed by diverse immunological side effects known as immune-related adverse events (irAE). Currently, the toxicity of irAE is limiting the usage of ICIs. Here, we studied circulating monocytic myeloid-derived suppressor cells (M-MDSCs) and T cells in course of irAE after the ICI therapy. Our longitudinal study involved 31 melanoma patients with and without adverse events during anti-PD-1 monotherapy or anti-CTLA-4/PD-1 combination therapy. Peripheral blood samples were analyzed before ICI start, during ICI treatment, at the time point of irAE and during immunosuppressive treatment to cure irAE. We observed an enhanced progression-free survival among patients with irAE. In patients with irAE, we found an upregulation of CD69 on CD8+ T cells and a decreased frequency of regulatory T cells (Tregs). Moreover, lower frequencies of Tregs correlated with more severe side effects. Patients treated with immunomodulatory drugs after irAE manifestation tend to show an elevated number of M-MDSCs during an immunosuppressive therapy. We suggest that an activation of CD8+ T cells and the reduction of Treg frequencies could be responsible for the development of irAE.
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Affiliation(s)
- Alisa Lepper
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Centre Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Rebekka Bitsch
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Centre Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Feyza Gül Özbay Kurt
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Centre Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Ihor Arkhypov
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Centre Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Samantha Lasser
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Centre Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Jochen Utikal
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Centre Mannheim, Mannheim, Germany
| | - Viktor Umansky
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
- DKFZ-Hector Cancer Institute at the University Medical Centre Mannheim, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
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19
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Zhou C, Li Y, Li J, Song B, Li H, Liang B, Gu S, Li H, Chen C, Li S, Peng C, Liu F, Xiao J, Long X, Li P, Xiong Z, Yi X, Liao W, Shi L. A Phase 1/2 Multicenter Randomized Trial of Local Ablation plus Toripalimab versus Toripalimab Alone for Previously Treated Unresectable Hepatocellular Carcinoma. Clin Cancer Res 2023; 29:2816-2825. [PMID: 37223896 DOI: 10.1158/1078-0432.ccr-23-0410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 04/05/2023] [Accepted: 05/17/2023] [Indexed: 05/25/2023]
Abstract
PURPOSE To assess the safety and efficacy of local ablation plus PD-1 inhibitor toripalimab in previously treated unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS In the multicenter, two-stage, and randomized phase 1/2 trial, patients were randomly assigned to receive toripalimab alone (240 mg, every 3 weeks), subtotal local ablation followed by toripalimab starting on post-ablation day 3 (Schedule D3), or on post-ablation day 14 (Schedule D14). The first endpoint of stage 1 was to determine which combination schedule could continue and progression-free survival (PFS) as the primary endpoint for stage 1/2. RESULTS A total of 146 patients were recruited. During stage 1, Schedule D3 achieved numerically higher objective response rate (ORR) than Schedule D14 for non-ablation lesions (37.5% vs. 31.3%), and was chosen for stage 2 evaluation. For the entire cohort of both stages, patients with Schedule D3 had a significantly higher ORR than with toripalimab alone (33.8% vs. 16.9%; P = 0.027). Moreover, patients with Schedule D3 had improved median PFS (7.1 vs. 3.8 months; P < 0.001) and median overall survival (18.4 vs. 13.2 months; P = 0.005), as compared with toripalimab alone. In addition, six (9%) patients with toripalimab, eight (12%) with Schedule D3, and 4 (25%) with Schedule D14 developed grade 3 or 4 adverse events, and one patient (2%) with Schedule D3 manifested grade 5 treatment-related pneumonitis. CONCLUSIONS In patients with previously treated unresectable HCC, subtotal ablation plus toripalimab improved the clinical efficacy as compared with toripalimab alone, with an acceptable safety profile.
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Affiliation(s)
- Chunhui Zhou
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Yan Li
- Department of Vascular and Tumor Intervention, the First Affiliated Hospital, Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Jiaping Li
- Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Botian Song
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Hanfeng Li
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Bin Liang
- Department of Radiology, Hubei Key Laboratory of Molecular Imaging, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Changsha, China
| | - Shanzhi Gu
- Department of Interventional Radiology, Hunan Cancer Hospital of Xiangya School, Central South University, Changsha, China
| | - Haiping Li
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Changyong Chen
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Sai Li
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Changli Peng
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Fei Liu
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Juxiong Xiao
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Xueying Long
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Ping Li
- Department of Vascular and Tumor Intervention, the First Affiliated Hospital, Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Zhengping Xiong
- Department of Interventional Radiology, Hunan Cancer Hospital of Xiangya School, Central South University, Changsha, China
| | - Xiaoping Yi
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Weihua Liao
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
| | - Liangrong Shi
- Department of Radiology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
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20
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Liu C, Shatila M, Mathew A, Machado AP, Thomas A, Zhang HC, Thomas AS, Faleck D, Funchain P, Philpott J, Grivas P, Obeid M, Carbonnel F, Wang Y. Role of C-Reactive Protein in Predicting the Severity and Response of Immune-Mediated Diarrhea and Colitis in Patients with Cancer. J Cancer 2023; 14:1913-1919. [PMID: 37476185 PMCID: PMC10355204 DOI: 10.7150/jca.84261] [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: 03/13/2023] [Accepted: 05/07/2023] [Indexed: 07/22/2023] Open
Abstract
Background: Immune-mediated diarrhea and colitis (IMDC) frequently develop after treatment with immune checkpoint inhibitors. C-reactive protein (CRP) is a serum inflammatory biomarker used to stratify and monitor disease severity in many inflammatory conditions. However, CRP level is not specific and is widely influenced by various factors non-specific to bowel inflammation. We aimed to study the utility of CRP as a predictor of disease severity and therapy response in IMDC. Methods: We performed a retrospective analysis of patients diagnosed with IMDC who had CRP measured at IMDC onset and after treatment with selective immunosuppressive therapy (SIT: infliximab and vedolizumab), between 01/2016 and 02/2022 at MD Anderson Cancer Center. Patient demographics, clinical characteristics, and IMDC data were collected and analyzed. Results: Our sample of 128 patients had a median age of 67 years; most were white (89.8%); and male (65.6%). Prior to development of IMDC, 15 (11.7%) were initially treated with anti-CTLA-4, 42 (32.8%) with anti-PD-1 or PD-L1, and 71 (55.5%) with a combination of both. We found higher CRP level was associated with higher CTCAE grade of clinical symptoms such as diarrhea (p=0.015), colitis (p=0.013), and endoscopic findings (p=0.016). While CRP levels decreased after IMDC treatment, there was no significant association between CRP levels with clinical remission, endoscopic remission or histologic remission. There also was no significant correlation between CRP level and recurrence of IMDC, or with fecal calprotectin levels. Conclusion: CRP level may be useful to assess initial severity of IMDC, including grade of diarrhea and colitis and degree of endoscopic inflammation. However, CRP is not a robust surrogate biomarker for assessing treatment response or disease recurrence. Despite the reduction of CRP levels observed following IMDC treatment, this finding might be nonspecific and potentially confounded by concurrent clinical factors, such as underlying malignancy, other inflammatory processes, and systemic anti-cancer therapy. Further studies of the role of CRP are warranted in patients with cancer and IMDC.
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Affiliation(s)
- Cynthia Liu
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Malek Shatila
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Antony Mathew
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Antonio Pizuorno Machado
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Austin Thomas
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Hao Chi Zhang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha S. Thomas
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David Faleck
- Gastroenterology, Hepatology and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Pauline Funchain
- Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA
| | - Jessica Philpott
- Center for Inflammatory Bowel Disease, Cleveland Clinic, Cleveland, OH, USA
| | - Petros Grivas
- Department of Medicine, Division of Oncology, University of Washington, Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Michel Obeid
- Centre Hospitalier Universitaire Vaudois, Department of Medicine, Service of Immunology and Allergy, Lausanne, Switzerland
| | - Franck Carbonnel
- Gastroenterology Department, Université Paris Saclay 11, Le Kremlin-Bicêtre, France
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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21
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Yamamoto T, Mizuno K, Ito T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Honda T, Ishikawa T, Kanamori A, Yasuda S, Toyoda H, Yokota K, Hase T, Nishio N, Maeda O, Ishii M, Sone M, Ando Y, Akiyama M, Ishigami M, Kawashima H. Abdominal pain accompanied by elevated serum inflammatory markers and biliary enzymes for diagnosing immune checkpoint inhibitor-induced sclerosing cholangitis. Invest New Drugs 2023:10.1007/s10637-023-01366-3. [PMID: 37171720 DOI: 10.1007/s10637-023-01366-3] [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: 04/06/2023] [Accepted: 04/24/2023] [Indexed: 05/13/2023]
Abstract
Immune-related sclerosing cholangitis (irSC) is relatively rare and its clinical characteristics are not well known. In this study, we aimed to summarize the clinical features of irSC. Clinical data were collected retrospectively from 1,393 patients with advanced malignancy treated with immune-checkpoint inhibitors (ICIs) between August 2014 and October 2021. We analyzed patients with immune-related adverse events of liver injury (liver-irAEs) and compared irSC and non-irSC groups. Sixty-seven patients (4.8%) had a liver-irAE (≥ grade 3) during the follow-up period (median, 262 days). Among these, irSC was observed in eight patients (11.9%). All patients in the irSC group were treated with anti-PD-1/PD-L1 antibodies. Compared with the non-irSC group, the irSC group showed mainly non-hepatocellular liver injury (87.5 % vs 50.8 %, P = 0.065), and had elevated serum inflammatory markers (e.g., CRP and NLR) and biliary enzymes (e.g., GGTP and ALP) at the onset of liver-irAEs. Furthermore, most patients with irSC had abdominal pain. In the non-irSC group, the liver injury of 23 patients improved only with the discontinuation of ICIs, and 22 patients improved with medication including prednisolone (PSL). Conversely, almost all patients (n=7) in the irSC group were treated with PSL, but only two patients experienced an improvement in liver injury. We found that irSC is characterized by a non-hepatocellular type of liver injury with abdominal pain and a high inflammatory response and is refractory to treatment. Further examination by imaging is recommended to detect intractable irSC in cases with these characteristics.
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Affiliation(s)
- Takafumi Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuyuki Mizuno
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Shinya Yokoyama
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norihiro Imai
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Kanamori
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Kenji Yokota
- Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsunari Hase
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naoki Nishio
- Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Osamu Maeda
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | - Makoto Ishii
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michihiko Sone
- Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuichi Ando
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan
| | - Masashi Akiyama
- Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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22
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Tomsitz D, Ruf T, Zierold S, French LE, Heinzerling L. Steroid-Refractory Immune-Related Adverse Events Induced by Checkpoint Inhibitors. Cancers (Basel) 2023; 15:cancers15092538. [PMID: 37174003 PMCID: PMC10177379 DOI: 10.3390/cancers15092538] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/23/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
The occurrence, second-line management and outcome of sr/sd-irAEs was investigated in patients with skin cancer. All skin cancer patients treated with immune checkpoint inhibitors (ICIs) between 2013 and 2021 at a tertiary care center were analyzed retrospectively. Adverse events were coded by CTCAE version 5.0. The course and frequency of irAEs were summarized using descriptive statistics. A total of 406 patients were included in the study. In 44.6% (n = 181) of patients, 229 irAEs were documented. Out of those, 146 irAEs (63.8%) were treated with systemic steroids. Sr-irAEs and sd-irAEs (n = 25) were detected in 10.9% of all irAEs, and in 6.2% of ICI-treated patients. In this cohort, infliximab (48%) and mycophenolate mofetil (28%) were most often administered as second-line immunosuppressants. The type of irAE was the most important factor associated with the choice of second-line immunosuppression. The Sd/sr-irAEs resolved in 60% of cases, had permanent sequelae in 28% of cases, and required third-line therapy in 12%. None of the irAEs were fatal. Although these side effects manifest in only 6.2% of patients under ICI therapy, they impose difficult therapy decisions, especially since there are few data to determine the optimal second-line immunosuppression.
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Affiliation(s)
- Dirk Tomsitz
- Department of Dermatology and Allergy, University Hospital, LMU Munich, 80539 Munich, Germany
| | - Theresa Ruf
- Department of Dermatology and Allergy, University Hospital, LMU Munich, 80539 Munich, Germany
- SERIO Side Effects Registry Immunooncology, 80337 Munich, Germany
| | - Sarah Zierold
- Department of Dermatology and Allergy, University Hospital, LMU Munich, 80539 Munich, Germany
- SERIO Side Effects Registry Immunooncology, 80337 Munich, Germany
| | - Lars E French
- Department of Dermatology and Allergy, University Hospital, LMU Munich, 80539 Munich, Germany
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Lucie Heinzerling
- Department of Dermatology and Allergy, University Hospital, LMU Munich, 80539 Munich, Germany
- SERIO Side Effects Registry Immunooncology, 80337 Munich, Germany
- Department of Dermatology and Allergy, University Hospital Erlangen, 91054 Erlangen, Germany
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23
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Les I, Martínez M, Pérez-Francisco I, Cabero M, Teijeira L, Arrazubi V, Torrego N, Campillo-Calatayud A, Elejalde I, Kochan G, Escors D. Predictive Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Events. Cancers (Basel) 2023; 15:1629. [PMID: 36900420 PMCID: PMC10000735 DOI: 10.3390/cancers15051629] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/24/2023] [Accepted: 02/28/2023] [Indexed: 03/09/2023] Open
Abstract
Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as the cytotoxic T-lymphocyte-associated antigen-4, the programmed cell death protein-1 and its ligand PD-L1, and they are increasingly used in cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell activation and antitumor activity but may induce so-called immune-related adverse events (irAEs), which mimic traditional autoimmune disorders. With the approval of more ICIs, irAE prediction has become a key factor in improving patient survival and quality of life. Several biomarkers have been described as potential irAE predictors, some of them are already available for clinical use and others are under development; examples include circulating blood cell counts and ratios, T-cell expansion and diversification, cytokines, autoantibodies and autoantigens, serum and other biological fluid proteins, human leucocyte antigen genotypes, genetic variations and gene profiles, microRNAs, and the gastrointestinal microbiome. Nevertheless, it is difficult to generalize the application of irAE biomarkers based on the current evidence because most studies have been retrospective, time-limited and restricted to a specific type of cancer, irAE or ICI. Long-term prospective cohorts and real-life studies are needed to assess the predictive capacity of different potential irAE biomarkers, regardless of the ICI type, organ involved or cancer site.
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Affiliation(s)
- Iñigo Les
- Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Autoimmune Diseases Unit, Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Inflammatory and Immune-Mediated Diseases Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - Mireia Martínez
- Osakidetza Basque Health Service, Department of Medical Oncology, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain
- Lung Cancer Research Group, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - Inés Pérez-Francisco
- Breast Cancer Research Group, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - María Cabero
- Clinical Trials Platform, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - Lucía Teijeira
- Medical Oncology Department, Navarre University Hospital, 31008 Pamplona, Spain
| | - Virginia Arrazubi
- Medical Oncology Department, Navarre University Hospital, 31008 Pamplona, Spain
| | - Nuria Torrego
- Osakidetza Basque Health Service, Department of Medical Oncology, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain
- Lung Cancer Research Group, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - Ana Campillo-Calatayud
- Inflammatory and Immune-Mediated Diseases Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - Iñaki Elejalde
- Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Autoimmune Diseases Unit, Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Inflammatory and Immune-Mediated Diseases Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - Grazyna Kochan
- Oncoimmunology Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - David Escors
- Oncoimmunology Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
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24
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Evaluation and management of acute high-grade immunotherapy-related neurotoxicity. Heliyon 2023; 9:e13725. [PMID: 36851967 PMCID: PMC9958505 DOI: 10.1016/j.heliyon.2023.e13725] [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: 06/30/2022] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Immune checkpoint inhibitor monoclonal antibodies allow the host's immune system to attack tumors, which has revolutionized cancer care over the last decade. As the use of immune checkpoint inhibitors has expanded, so have autoimmune-like complications known as immune-related adverse events. These include the infrequent but increasingly more common, potentially deadly neurological immune related adverse events. When feeling acutely ill, patients will often seek care not from their oncologist but from their family physician, clinics, emergency, and urgent care sites, or other available providers. Thus, while assessing acutely ill cancer patients who are experiencing neurological symptoms, non-oncologists should be prepared to recognize, diagnose, and treat neurological immune related adverse events in addition to more familiar conditions. This narrative review is designed to update acute care clinicians on current knowledge and to present a symptom-based framework for evaluating and treating neurological immune related adverse events based on the leading immunotoxicity organizations' latest recommendations.
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25
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Burzio C, Balzani E, Montrucchio G, Trompeo AC, Corcione S, Brazzi L. Trichoderma spp.-Related Pneumonia: A Case Report in Heart-Lung Transplantation Recipient and a Systematic Literature Review. J Fungi (Basel) 2023; 9:195. [PMID: 36836310 PMCID: PMC9961996 DOI: 10.3390/jof9020195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/26/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Opportunistic and hospital-acquired infections are common among recipients of solid organ transplantation. New pathogens are increasingly reported in the intensive care unit (ICU) population. We report a case of a patient who developed Trichoderma spp.-related pneumonia (TRP) after heart-lung transplantation. In the absence of antifungal susceptibility testing, TRP was confirmed by histological examination, and empirical therapy with voriconazole and caspofungin was swiftly initiated. Complete resolution of pneumonia was obtained after prolonged combination therapy. Given the lack of guidelines, we conducted a systematic review to elucidate the diagnostic and therapeutic strategies to apply during Trichoderma infection. After deduplication and selection of full texts, we found 42 articles eligible for the systematic review. Pneumonia seems to be the most common clinical manifestation (31.8%). The most used antifungal therapy was amphotericin B, while combination therapy was also reported (27.3%). All the patients were immunocompromised except for one case. Despite the rarity of Trichoderma spp. infection, the increase in invasive fungal infections is of growing importance in ICU, considering their impact on mortality and the emergence of antifungal resistance. In the absence of prospective and multicenter studies, a review can provide useful insight regarding the epidemiology, clinical manifestations, and management of these unexpected challenges.
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Affiliation(s)
- Carlo Burzio
- Department of Anesthesia, Intensive Care and Emergency, Città della Salute e della Scienza di Torino Hospital, 10126 Torino, Italy
| | - Eleonora Balzani
- Department of Surgical Science, University of Turin, 10124 Torino, Italy
| | - Giorgia Montrucchio
- Department of Anesthesia, Intensive Care and Emergency, Città della Salute e della Scienza di Torino Hospital, 10126 Torino, Italy
- Department of Surgical Science, University of Turin, 10124 Torino, Italy
| | - Anna Chiara Trompeo
- Department of Anesthesia, Intensive Care and Emergency, Città della Salute e della Scienza di Torino Hospital, 10126 Torino, Italy
| | - Silvia Corcione
- Department of Medical Sciences, Infectious Diseases, University of Turin, 10124 Turin, Italy
- School of Medicine, Tufts University, Boston, MA 02111, USA
| | - Luca Brazzi
- Department of Anesthesia, Intensive Care and Emergency, Città della Salute e della Scienza di Torino Hospital, 10126 Torino, Italy
- Department of Surgical Science, University of Turin, 10124 Torino, Italy
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26
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Franciosa G, Kverneland AH, Jensen AWP, Donia M, Olsen JV. Proteomics to study cancer immunity and improve treatment. Semin Immunopathol 2023; 45:241-251. [PMID: 36598558 PMCID: PMC10121539 DOI: 10.1007/s00281-022-00980-2] [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: 12/02/2022] [Accepted: 12/12/2022] [Indexed: 01/05/2023]
Abstract
Cancer survival and progression depend on the ability of tumor cells to avoid immune recognition. Advances in the understanding of cancer immunity and tumor immune escape mechanisms enabled the development of immunotherapeutic approaches. In patients with otherwise incurable metastatic cancers, immunotherapy resulted in unprecedented response rates with the potential for durable complete responses. However, primary and acquired resistance mechanisms limit the efficacy of immunotherapy. Further therapeutic advances require a deeper understanding of the interplay between immune cells and tumors. Most high-throughput studies within the past decade focused on an omics characterization at DNA and RNA level. However, proteins are the molecular effectors of genomic information; therefore, the study of proteins provides deeper understanding of cellular functions. Recent advances in mass spectrometry (MS)-based proteomics at a system-wide scale may allow translational and clinical discoveries by enabling the analysis of understudied post-translational modifications, subcellular protein localization, cell signaling, and protein-protein interactions. In this review, we discuss the potential contribution of MS-based proteomics to preclinical and clinical research findings in the context of tumor immunity and cancer immunotherapies.
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Affiliation(s)
- Giulia Franciosa
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
| | - Anders H Kverneland
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.,National Center of Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
| | - Agnete W P Jensen
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Marco Donia
- National Center of Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark
| | - Jesper V Olsen
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
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27
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Schlüter J, Cunningham S, Zimmermann R, Achenbach S, Kramer R, Erdmann M, Beckmann M, Heinzerling L, Hackstein H. Characterization of the impact of immune checkpoint inhibitors on platelet activation and aggregation. Immunobiology 2023; 228:152311. [PMID: 36495598 DOI: 10.1016/j.imbio.2022.152311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/18/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Immune checkpoint inhibitors (ICIs) are effective oncological drugs which block cellular check-point receptors typically targeted by tumor immune evasion strategies. Despite their benefits, clinicians have reported treatment-associated thromboembolism during ICI therapy in recent years. Though several theories on this ICI-associated pathogenesis exist, the direct effects of ICIs on platelets remains unknown. We therefore investigated the potential direct and indirect effect of PD-1, PD-L1 and CTLA-4-targeting ICIs on platelet functionality in multifaceted in vitro experiments. Interestingly, we could not observe a clear effect of ICI on platelet aggregation and primary hemostasis in whole blood and platelet concentrate-based assays. Furthermore, the presence of ICIs in toll-like receptor stimulation had no significant impact on platelet surface marker expression. In a second approach, we investigated the indirect immunological impact of ICIs on platelet activation by exposing platelets to supernatants from ICI- and Staphylococcal enterotoxin B-exposed PBMCs. Whereas ICIs affected IL-2 levels in supernatants, we could not detect clear differences in the secretion of pro-thrombogenic factors and platelet responses. The obtained data suggest that the direct influence of ICIs on platelet activation or the influence of altered T cell function on platelet activation cannot be considered a major factor in the development of thrombotic events.
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Affiliation(s)
- Julian Schlüter
- Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, Erlangen 91054, Germany
| | - Sarah Cunningham
- Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, Erlangen 91054, Germany.
| | - Robert Zimmermann
- Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, Erlangen 91054, Germany
| | - Susanne Achenbach
- Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, Erlangen 91054, Germany
| | - Rafaela Kramer
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen 91054, Germany
| | - Michael Erdmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen 91054, Germany
| | - Malte Beckmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen 91054, Germany
| | - Lucie Heinzerling
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen 91054, Germany; Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich 80539, Germany
| | - Holger Hackstein
- Department of Transfusion Medicine and Hemostaseology, University Hospital Erlangen, Erlangen 91054, Germany
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28
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Immune-checkpoint inhibitor use in patients with cancer and pre-existing autoimmune diseases. Nat Rev Rheumatol 2022; 18:641-656. [PMID: 36198831 DOI: 10.1038/s41584-022-00841-0] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2022] [Indexed: 11/08/2022]
Abstract
Immune-checkpoint inhibitors (ICIs) have dramatically changed the management of advanced cancers. Designed to enhance the antitumour immune response, they can also cause off-target immune-related adverse events (irAEs), which are sometimes severe. Although the efficacy of ICIs suggests that they could have wide-ranging benefits, clinical trials of the drugs have so far excluded patients with pre-existing autoimmune disease. However, evidence is accumulating with regard to the use of ICIs in this 'at-risk' population, with retrospective data suggesting that they have an acceptable safety profile, but that there is a risk of disease flare or other irAE occurrence. The management of immunosuppressive drugs at ICI initiation in patients with autoimmune disease (or later in instances of disease flare or irAE) remains a question of particular interest in clinical practice, in which there is always a search for the balance between protecting against autoimmunity and ensuring a good tumour response. Although temporary use of immunosuppressants seems safe, prolonged use or use at ICI initiation might hamper the antitumour immune response, prompting clinicians to use the minimal efficient immunosuppressive regimen. However, a new paradigm is emerging, in which inhibitors of TNF or IL-6 could have synergistic effects with ICIs on tumour response, while also preventing severe irAEs. If confirmed, this 'decoupling' effect on toxicity and efficacy could change therapeutic practice in this field. Knowledge of the current use of ICIs in patients with pre-existing autoimmune disease, particularly with regard to the use of immunosuppressive drugs and/or biologic DMARDs, can help to guide clinical practice.
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29
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Fan S, Liu X, Wu Y, Li K, Zhao X, Lin W, Liu J. Prognostic Value of Lactate Dehydrogenase, Melanoma Inhibitory Protein, and S-100B Protein in Patients with Malignant Melanoma. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:9086540. [PMID: 36248431 PMCID: PMC9553451 DOI: 10.1155/2022/9086540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/11/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022]
Abstract
Objective This investigation probed the prognostic potential for lactate dehydrogenase (LDH), melanoma inhibitory activity protein (MIA), and S-100B protein in cases of malignant melanoma. Methods 84 cases were segregated into effective cohort (n = 64) and ineffective cohort (n = 20) depending on clinical efficacy. The cases were followed up for three years and segregated into mortality cohort (n = 29) and survival cohort (n = 55) depending upon 3-year survival. Serum LDH, MIA, and S-100B levels were compared across the effective and ineffective cohorts. Serum LDH, MIA, and S-100B levels in cases of different clinical stages were comparatively analyzed, with correlations of these indicators with the clinical stage being evaluated. ROC evaluated the prognostic potential of serum LDH, MIA, and S-100B. Cases were segregated into the high-level and low-level cohorts according to serum LDH, MIA, and S-100B levels, and the survival rates of cases were compared. Results The levels of LDH, MIA, and S-100B in the effective cohort were significantly lower than those in the ineffective cohort. The AUC value of the composite indicator of serum LDH, MIA, and S-100B for effectiveness evaluation was (0.839). Serum LDH, MIA, and S-100B levels were positively linked to the clinical stage. AUC value of the composite indicator of serum LDH, MIA, and S-100B for prognosis evaluation prediction (0.942) was elevated compared to LDH (0.632), MIA (0.732), or S-100B (0.828) alone. Survival rate of cases of LDH ≥30.56 mg/L (57.14%, 32/56) was lower than that of cases of LDH <30.56 mg/L (82.14%, 23/28) (log-rank χ 2 = 4.672, P < 0.05). The survival rate of MIA ≥5.34 ng/mL cases was lower than that of MIA <5.34 ng/mL cases. The survival rate of cases of S-100B ≥ 1.03ug/L was lower than that of S-100B < 1.03ug/L. Conclusion Serum LDH, MIA, and S-100B protein levels are linked to the clinical stage. The lactate dehydrogenase, melanoma inhibitory protein, and S-100B protein are of good clinical effectiveness and have the prognostic potential for cases of malignant melanoma.
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Affiliation(s)
- Shuwen Fan
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China
| | - Xiao Liu
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China
| | - Yizhu Wu
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China
| | - Ke Li
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China
| | - Xiaoyu Zhao
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China
| | - Wei Lin
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China
| | - Jianjiang Liu
- Department of Burn and Plastic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, China
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30
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Garrison Z, Hornick N, Cheng J, Kulkarni RP. Circulating biomarkers of response to immunotherapy and immune-related adverse events. Expert Rev Mol Diagn 2022; 22:855-865. [PMID: 36193802 DOI: 10.1080/14737159.2022.2130688] [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: 01/08/2023]
Abstract
INTRODUCTION Immune checkpoint blockade has revolutionized cancer treatment. However, response rates vary, and these treatments have a high rate of immune-related side effects, which can be limiting. Thus, tests to predict who will respond and who may experience side effects are of critical importance toward realizing the ultimate goal of precision oncology. AREAS COVERED We review several of the most recent advances in circulating biomarkers that have been reported to be useful in predicting response and immune-related adverse events (irAE) to checkpoint blockade immunotherapies (CBI). We focus on high-quality studies published within the last few years. We highlight significant findings, identify areas for improvement, and provide recommendations on how these biomarkers may be translated into clinical utility. EXPERT OPINION As newer immunotherapies are developed, there is a pressing need to identify circulating biomarkers that can help predict responses and side effects. Current studies are mostly small-scale and retrospective; there is a need for larger-scale and prospective studies to help validate several of the biomarkers detailed here. As oncology focuses more on precision-based approaches, it is likely that a combination of biomarkers, including circulating ones as detailed here, will have critical utility in guiding clinical decisions.
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Affiliation(s)
- Zachary Garrison
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA
| | - Noah Hornick
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA
| | - Jeffrey Cheng
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Rajan P Kulkarni
- Department of Dermatology, Oregon Health & Science University, Portland, OR, USA.,Cancer Early Detection Advanced Research Center (CEDAR), Portland, OR, USA.,Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.,Operative Care Division, U.S. Department of Veterans Affairs Portland Health Care System, Portland, OR, USA
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31
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Peripheral Blood Biomarkers Predictive of Efficacy Outcome and Immune-Related Adverse Events in Advanced Gastrointestinal Cancers Treated with Checkpoint Inhibitors. Cancers (Basel) 2022; 14:cancers14153736. [PMID: 35954401 PMCID: PMC9367581 DOI: 10.3390/cancers14153736] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 07/20/2022] [Accepted: 07/27/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Gastrointestinal cancers constitute a major burden of global cancer mortalities. In recent years, the advent of immune checkpoint inhibitors has greatly improved the survival of patients with advanced gastrointestinal cancers, while predictive biomarkers of treatment efficacy and toxicities are still unmet demands. Methods: In our retrospective study, patients with advanced gastrointestinal cancers who received single or double immune checkpoint inhibitors in the Department of Gastrointestinal Oncology in Peking University Cancer Hospital between July 2016 and February 2022 were enrolled. Records of clinicopathological information, survival parameters, safety data, and baseline and posttreatment peripheral blood constituents were retrieved. Cox regression analysis and logistic regression analysis were performed to identify the predictive factors of treatment outcomes and immune-related adverse events. Results: We demonstrated that early treatment lines, the presence of immune-related adverse events, and a lower C2 neutrophil-to-lymphocyte ratio were independent factors predicting a superior objective response rate and progression-free survival in patients treated with immunotherapy. Lower ECOG PS, higher baseline albumin, and lower C2 neutrophil-to-lymphocyte ratios were independent risk factors for the onset of immune-related adverse events. Patients who succumbed to immune-related adverse events during immunotherapy presented better survival. Conclusion: Our results indicate that peripheral blood markers have potential for predicting treatment outcomes and immune-related adverse events in patients with advanced gastrointestinal cancer. Prospective validations are warranted.
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32
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Chan KK, Bass AR. Monitoring and Management of the Patient with Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis: Current Perspectives. J Inflamm Res 2022; 15:3105-3118. [PMID: 35642215 PMCID: PMC9148583 DOI: 10.2147/jir.s282600] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/18/2022] [Indexed: 11/23/2022] Open
Abstract
In this review, we draw from observational studies, treatment guidelines and our own clinical experience to describe approaches to monitoring and management of immune checkpoint inhibitor (ICI)-induced inflammatory arthritis, including polymyalgia rheumatica. This condition occurs in about 4% of ICI-treated cancer patients and can persist for a year or longer. Mild arthritis can generally be managed with non-steroidal anti-inflammatory drugs, intraarticular steroids injections and/or low dose corticosteroids. Higher grade arthritis should be brought under control with corticosteroids, but early introduction of a steroid-sparing agent is recommended to minimize steroid toxicity. In order to assess the effectiveness of any arthritis treatment, tender and swollen joint counts and patient reported measures of physical function, such as the health assessment questionnaire, should be obtained at each visit. Referral to a rheumatologist is recommended for patients with high grade arthritis to help guide the use of disease-modifying antirheumatic drugs.
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Affiliation(s)
- Karmela K Chan
- Department of Medicine, Hospital for Special Surgery/Weill Cornell Medicine, New York, NY, USA
| | - Anne R Bass
- Department of Medicine, Hospital for Special Surgery/Weill Cornell Medicine, New York, NY, USA
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33
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Lin X, Deng H, Yang Y, Wu J, Qiu G, Li S, Xie X, Liu M, Xie Z, Qin Y, Song Y, Zhou C. Peripheral Blood Biomarkers for Early Diagnosis, Severity, and Prognosis of Checkpoint Inhibitor-Related Pneumonitis in Patients With Lung Cancer. Front Oncol 2021; 11:698832. [PMID: 34327140 PMCID: PMC8313853 DOI: 10.3389/fonc.2021.698832] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 06/24/2021] [Indexed: 12/16/2022] Open
Abstract
Background Checkpoint inhibitor-related pneumonitis (CIP) is a potentially fatal immune-related adverse event that occurs during treatment with immune checkpoint inhibitors (ICIs). However, the roles played by peripheral blood parameters in CIP development remain unclear. Here, we aimed to identify which blood biomarkers correlated with the development and prognosis of CIP in patients with lung cancer. Methods We conducted a retrospective analysis of 87 patients with CIP (CIP group) and 87 patients without CIP (control group). Cytokines, blood routine, lactate dehydrogenase (LDH) and albumin (ALB) were collected at baseline (before ICIs), at onset of pneumonitis (in the CIP group), and before the last dose of ICI (in the control group). We compared the baseline values and changes over time in various blood parameters between the CIP and control groups. The CIP outcomes were collected and compared according to the median values of these parameters. Results Squamous carcinoma (odds ratio [OR]: 3.02; p = 0.004) and ICI monotherapy (OR: 6.56; p = 0.004) correlated with a high risk of CIP. In the CIP group, interleukin (IL)-6 and platelet-to-lymphocyte ratio (PLR) at CIP were significantly increased relative to baseline. By contrast, IL-6 and PLR reduced over time in the control group. Significant decrease in absolute lymphocyte count (ALC) and increases in IL-10, neutrophil to lymphocyte ratio (NLR), and LDH levels were observed from baseline to CIP. No significant change in these parameters was observed in the control group relative to baseline. ALB decreased in both groups, but the decrease in the CIP group was greater (9.21% vs. 2.44%; p = 0.020). High IL-6 levels (OR: 5.23, 95% confidence interval [CI]: 1.15–23.86; p = 0.033), and low levels of ALB (OR: 0.16, 95% CI: 0.04–0.64; p = 0.009) measured at the time of CIP symptom onset were associated with severe pneumonitis. Low concentration of IL-6 (hazard ratio [HR]: 0.17, 95% CI: 0.03–0.95; p = 0.044) and high ALB levels (HR: 0.28, 95% CI: 0.08–0.94; p = 0.040) were correlated with favorable overall survival in CIP. Conclusions Increase in IL-6, IL-10, NLR, PLR, and LDH levels or reduced ALC and ALB levels were associated with the occurrence of CIP in lung cancer patients. High IL-6 and low ALB levels at onset of CIP were related to severe grade and poor prognosis of CIP.
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Affiliation(s)
- Xinqing Lin
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Haiyi Deng
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yilin Yang
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jianhui Wu
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Guihuan Qiu
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Suyang Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xiaohong Xie
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ming Liu
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhanhong Xie
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yinyin Qin
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing, China
| | - Chengzhi Zhou
- State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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34
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Kurzhals JK, Graf T, Boch K, Grzyska U, Frydrychowicz A, Zillikens D, Terheyden P, Langan EA. Serum Troponin T Concentrations Are Frequently Elevated in Advanced Skin Cancer Patients Prior to Immune Checkpoint Inhibitor Therapy: Experience From a Single Tertiary Referral Center. Front Med (Lausanne) 2021; 8:691618. [PMID: 34291066 PMCID: PMC8288046 DOI: 10.3389/fmed.2021.691618] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 04/20/2021] [Indexed: 01/22/2023] Open
Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several human malignancies, particularly metastatic skin cancer. However, immune-related myocarditis (irM), an immune-mediated adverse event (irAE), is often fatal. In the absence of a reliable biomarker, measurement of pre-ICI therapy serum troponin concentration has been proposed to identify patients at risk of developing irM, although real-world studies examining this strategy are lacking. Thus, we retrospectively analyzed the case records of all patients who commenced ICI therapy between January 2018 and December 2019 in a single university skin cancer center (n = 121) to (i) determine the incidence of irM, (ii) establish the frequency of pretreatment serum hsTnT elevations, and (iii) to establish whether this identified patients who subsequently developed irM. Only one patient developed irM, resulting in an overall incidence of 0.8%. Pretreatment hsTnT was measured in 47 patients and was elevated in 13 (28%). Elevated serum hsTnT concentrations were associated with chronic renal failure (p = 0.02) and diabetes (p < 0.0002). Pretreatment hsTnT was not elevated in the patient who developed fulminant irM. Pre-immunotherapy serum hsTnT concentrations were often asymptomatically elevated in patients with advanced skin cancer, none of whom subsequently developed irM during ICI therapy. However, large studies are required to assess the positive and negative predictive values of hsTnT for the development of irM. In the meantime, elevated hsTnT concentrations should be investigated before initiation of immunotherapy and closely monitored during early treatment cycles, where the risk of irM is greatest.
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Affiliation(s)
- Jonas K Kurzhals
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - Tobias Graf
- Department of Cardiology, University of Lübeck, Lübeck, Germany
| | - Katharina Boch
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - Ulrike Grzyska
- Department of Radiology and Nuclear Medicine, University of Lübeck, Lübeck, Germany
| | - Alex Frydrychowicz
- Department of Radiology and Nuclear Medicine, University of Lübeck, Lübeck, Germany
| | - Detlef Zillikens
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | | | - Ewan A Langan
- Department of Dermatology, University of Lübeck, Lübeck, Germany.,Dermatological Sciences, University of Manchester, Manchester, United Kingdom
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