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Yang J, Liu Z, Hu X, Zhang X, Huang Y, Chen Y, Chen C, Shang R, Tang Y, Hu W, Wang J, Shen HM, Hu J, He W. Skin-Resident γδ T Cells Mediate Potent and Selective Antitumor Cytotoxicity through Directed Chemotactic Migration and Mobilization of Cytotoxic Granules. J Invest Dermatol 2025; 145:1433-1446.e2. [PMID: 39571888 DOI: 10.1016/j.jid.2024.10.607] [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: 04/09/2024] [Revised: 09/15/2024] [Accepted: 10/03/2024] [Indexed: 12/25/2024]
Abstract
Dendritic epidermal T cells (DETCs) are a unique subset of γδ T cells that reside predominantly in mouse epidermis; yet, their antitumor functions remain enigmatic. In this study, we report that DETCs mediate potent and exquisitely selective cytotoxicity against diverse tumor types while sparing healthy cells. In vitro, DETCs induced apoptosis in melanoma, hepatoma, colon carcinoma, and lymphoma lines in a dose- and time-dependent manner that required direct cell-cell contact. In vivo, adoptive DETC transfer significantly suppressed melanoma growth and metastasis while prolonging survival. Mechanistically, DETCs upregulated perforin/granzyme B expression upon tumor recognition, and inhibition of this pathway ablated cytotoxicity. DETCs selectively homed to and formed intimate contacts with tumor cells in vivo through directed chemotaxis and aggregation. Tumor engagement triggered proinflammatory DETC activation while dampening immunosuppressive factors in the microenvironment. Notably, mTOR signaling coupled tumor recognition to DETC trafficking, cytotoxicity, and inflammatory programs because rapamycin treatment impaired effector functions and therapeutic efficacy. Collectively, these findings establish DETCs as multidimensional antitumor effectors and provide insights for harnessing their unique biology for cancer immunotherapy.
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Affiliation(s)
- Jiacai Yang
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Tissue Damage Repair and Regeneration, Chongqing, China
| | - Zhihui Liu
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Tissue Damage Repair and Regeneration, Chongqing, China
| | - Xiaohong Hu
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Tissue Damage Repair and Regeneration, Chongqing, China
| | - Xiaorong Zhang
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Tissue Damage Repair and Regeneration, Chongqing, China
| | - Yong Huang
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Tissue Damage Repair and Regeneration, Chongqing, China
| | - Yunxia Chen
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Tissue Damage Repair and Regeneration, Chongqing, China
| | - Cheng Chen
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Ruoyu Shang
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yuanyang Tang
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Wengang Hu
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jue Wang
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Han-Ming Shen
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China
| | - Jun Hu
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
| | - Weifeng He
- Institute of Burn Research, State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Chongqing Key Laboratory for Tissue Damage Repair and Regeneration, Chongqing, China.
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Majenka P, Hoffmann M, Strobel S, Rötzer I, Enk A, Hassel JC. Influence of high-fiber diet on ipilimumab-induced gastrointestinal toxicity in metastatic melanoma. Clin Nutr ESPEN 2025; 67:660-664. [PMID: 40112923 DOI: 10.1016/j.clnesp.2025.03.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND The anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 antibody ipilimumab (ipi) and the anti-programmed death (PD)-1 antibody nivolumab (nivo) are routinely used to treat metastatic melanoma. One of the most frequent severe immune-related adverse events (irAEs) induced by ipi is diarrhea as a symptom of ir-colitis. Here, the composition of the gut microbiome was shown to correlate with the risk of developing colitis. Stimulated by a patient case and the knowledge that nutrition influences the gut microbiome, we performed a retrospective analysis to evaluate dietary habits and the frequency of colitis in patients with ipi ± nivo therapy. METHODS Patients with metastasized stage III or IV melanoma who were treated with ipi ± nivo and who were willing to take part in a nutritional survey and interview at least three months after the first ipi dose were included into the study. Dietary habits were investigated using the food frequency questionnaire (FFQ) and personal interviews. The calculated daily intake of calories, carbohydrates, fats, proteins, sugars, and dietary fiber was correlated with the development of ir-colitis. RESULTS 20 patients were included into this study, and all but one received ipi-nivo combination therapy. The median age was 59.5 years, and 60 % were male. 4 of 20 patients (20 %) developed ir-colitis grade 3 after two cycles in the median and were managed with at least high-dose corticosteroids. The FFQ and interview were conducted in a median of six months after treatment initiation. In general, the interviewed patients followed a typical western-pattern diet based on carbohydrates as the main, followed by fat as the second most important energy substrate. Comparing patients with and without colitis our investigation revealed that the achieved amount of recommended dietary fiber intake per total energy intake (TEI) was negatively associated with diarrhea and colitis (p = 0.061). No significant differences concerning daily intake of calories, carbohydrates, fats, proteins, and sugar were found. In addition, no significant differences were found among patients in terms of their age, gender, tobacco use, supplement intake, therapy regime, or body mass index (BMI). CONCLUSIONS This pilot study gives first hints that nutritional habits might influence treatment tolerability to ipi ± nivo therapy. A high-fiber diet might protect against ir-colitis and diarrhea in ipi-treated patients. This observation should be validated by a prospective randomized interventional trial. However, if it is possible to prevent ir-colitis by a high-fiber diet that would be of great impact on routine patient treatment.
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Affiliation(s)
- Pawel Majenka
- Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership Between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | - Matthias Hoffmann
- Department of Nutrition Therapy, National Center for Tumor Diseases, Heidelberg, Germany
| | - Sophia Strobel
- Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership Between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | - Ingeborg Rötzer
- Department of Nutrition Therapy, National Center for Tumor Diseases, Heidelberg, Germany
| | - Alexander Enk
- Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership Between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | - Jessica C Hassel
- Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership Between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
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Peng J, Li S, Ti H. Sensitize Tumor Immunotherapy: Immunogenic Cell Death Inducing Nanosystems. Int J Nanomedicine 2024; 19:5895-5930. [PMID: 38895146 PMCID: PMC11184231 DOI: 10.2147/ijn.s457782] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Low immunogenicity of tumors poses a challenge in the development of effective tumor immunotherapy. However, emerging evidence suggests that certain therapeutic approaches, such as chemotherapy, radiotherapy, and phototherapy, can induce varying degrees of immunogenic cell death (ICD). This ICD phenomenon leads to the release of tumor antigens and the maturation of dendritic cells (DCs), thereby enhancing tumor immunogenicity and promoting immune responses. However, the use of a single conventional ICD inducer often fails to achieve in situ tumor ablation and establish long-term anti-tumor immune responses. Furthermore, the induction of ICD induction varies among different approaches, and the distribution of the therapeutic agent within the body influences the level of ICD and the occurrence of toxic side effects. To address these challenges and further boost tumor immunity, researchers have explored nanosystems as inducers of ICD in combination with tumor immunotherapy. This review examines the mechanisms of ICD and different induction methods, with a specific focus on the relationship between ICD and tumor immunity. The aim is to explore the research advancements utilizing various nanomaterials to enhance the body's anti-tumor effects by inducing ICD. This paper aims to contribute to the development and clinical application of nanomaterial-based ICD inducers in the field of cancer immunotherapy by providing important theoretical guidance and practical references.
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Affiliation(s)
- Jianlan Peng
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China
| | - Shiying Li
- Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China
| | - Huihui Ti
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China
- Guangdong Province Precise Medicine and Big Data Engineering Technology Research Center for Traditional Chinese Medicine, Guangzhou, People’s Republic of China
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Lu Q, Kou D, Lou S, Ashrafizadeh M, Aref AR, Canadas I, Tian Y, Niu X, Wang Y, Torabian P, Wang L, Sethi G, Tergaonkar V, Tay F, Yuan Z, Han P. Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy. J Hematol Oncol 2024; 17:16. [PMID: 38566199 PMCID: PMC10986145 DOI: 10.1186/s13045-024-01535-8] [Citation(s) in RCA: 118] [Impact Index Per Article: 118.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 03/15/2024] [Indexed: 04/04/2024] Open
Abstract
Cancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds. The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions, exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity, nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME modification.
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Affiliation(s)
- Qiang Lu
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, 569 Xinsi Road, Xi'an, 710038, China
| | - Dongquan Kou
- Department of Rehabilitation Medicine, Chongqing Public Health Medical Center, Chongqing, China
| | - Shenghan Lou
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Milad Ashrafizadeh
- Department of General Surgery, Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, 518055, Guangdong, China
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, 250000, Shandong, China
| | - Amir Reza Aref
- Xsphera Biosciences, Translational Medicine Group, 6 Tide Street, Boston, MA, 02210, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA
| | - Israel Canadas
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Yu Tian
- School of Public Health, Benedictine University, Lisle, USA
| | - Xiaojia Niu
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Yuzhuo Wang
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Pedram Torabian
- Cumming School of Medicine, Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, AB, T2N 4Z6, Canada
- Department of Medical Sciences, University of Calgary, Calgary, AB, T2N 4Z6, Canada
| | - Lingzhi Wang
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Singapore
| | - Gautam Sethi
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore, 117600, Singapore.
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, 138673, Singapore, Republic of Singapore
| | - Franklin Tay
- The Graduate School, Augusta University, 30912, Augusta, GA, USA
| | - Zhennan Yuan
- Department of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
| | - Peng Han
- Department of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China.
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Reddy YK, Fischer IS, Kolodney J, Willard M. A Curious Case of Gastrointestinal Eosinophilia Induced by Treatment With Immune Checkpoint Inhibitors. ACG Case Rep J 2023; 10:e01075. [PMID: 37324829 PMCID: PMC10266517 DOI: 10.14309/crj.0000000000001075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 05/15/2023] [Indexed: 06/17/2023] Open
Abstract
Immune checkpoint inhibitors have revolutionized oncologic treatment. However, they are linked to various side effects,1 a rare one being gastrointestinal eosinophilia. We present a patient with malignant melanoma treated with nivolumab. She underwent upper endoscopy 6 months later which showed a duodenal ulcer and linear furrows of her esophagus. Biopsies of the esophagus, stomach, and duodenum were consistent with eosinophilic infiltration. Repeat endoscopy after nivolumab discontinuation revealed near-complete resolution of eosinophilia in the stomach and duodenum, with lingering eosinophilia in the esophagus. The purpose of this report was to increase awareness of gastrointestinal eosinophilia associated with checkpoint inhibitors.
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Affiliation(s)
- Yala Kirthi Reddy
- Department of Gastroenterology, West Virginia University, Morgantown, WV
| | | | - Joanna Kolodney
- Department of Hematology and Oncology, West Virginia University, Morgantown, WV
| | - Megan Willard
- Department of Gastroenterology, West Virginia University, Morgantown, WV
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Suzuki K, Kunisada Y, Miyamura N, Eikawa S, Hurtado de Mendoza T, Mose ES, Lu C, Kuroda Y, Ruoslahti E, Lowy AM, Sugahara KN. Tumor-resident regulatory T cells in pancreatic cancer express the αvβ5 integrin as a targetable activation marker. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.24.542137. [PMID: 37292693 PMCID: PMC10245898 DOI: 10.1101/2023.05.24.542137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has abundant immunosuppressive regulatory T cells (Tregs), which contribute to a microenvironment resistant to immunotherapy. Here, we report that Tregs in the PDAC tissue, but not those in the spleen, express the αvβ5 integrin in addition to neuropilin-1 (NRP-1), which makes them susceptible to the iRGD tumor-penetrating peptide, which targets cells positive for αv integrin- and NRP-1. As a result, long-term treatment of PDAC mice with iRGD leads to tumor-specific depletion of Tregs and improved efficacy of immune checkpoint blockade. αvβ5 integrin + Tregs are induced from both naïve CD4 + T cells and natural Tregs upon T cell receptor stimulation, and represent a highly immunosuppressive subpopulation of CCR8 + Tregs. This study identifies the αvβ5 integrin as a marker for activated tumor-resident Tregs, which can be targeted to achieve tumor-specific Treg depletion and thereby augment anti-tumor immunity for PDAC therapy.
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Khadela A, Shah Y, Mistry P, Bodiwala K, CB A. Immunomodulatory Therapy in Head and Neck Squamous Cell Carcinoma: Recent Advances and Clinical Prospects. Technol Cancer Res Treat 2023; 22:15330338221150559. [PMID: 36683526 PMCID: PMC9893386 DOI: 10.1177/15330338221150559] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
The immune system plays a significant role in the development, invasion, progression, and metastasis of head and neck cancer. Over the last decade, the emergence of immunotherapy has irreversibly altered the paradigm of cancer treatment. The current treatment modalities for head and neck squamous cell carcinoma (HNSCC) include surgery, radiotherapy, and adjuvant or neoadjuvant chemotherapy which has failed to provide satisfactory clinical outcomes. To encounter this, there is a need for a novel or targeted therapy such as immunological targets along with conventional treatment strategy for optimal therapeutic outcomes. The immune system can contribute to promoting metastasis, angiogenesis, and growth by exploiting the tumor's influence on the microenvironment. Immunological targets have been found effective in recent clinical studies and have shown promising results. This review outlines the important immunological targets and the medications acting on them that have already been explored, are currently under clinical trials and are further being targeted.
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Affiliation(s)
- Avinash Khadela
- Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, India
| | - Yesha Shah
- Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, India
| | - Priya Mistry
- Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, India
| | - Kunjan Bodiwala
- Department of Pharmaceutical chemistry, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, India
| | - Avinash CB
- Medical Oncologist, ClearMedi Radiant Hospital, Mysore, India
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Clinical Manifestations, Diagnosis, Treatment and Prognosis of Uveitis Induced by Anticancer Drugs: A Review of Literature. Brain Sci 2022; 12:brainsci12091168. [PMID: 36138905 PMCID: PMC9497212 DOI: 10.3390/brainsci12091168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/25/2022] Open
Abstract
There are increasing reports that anticancer drugs, especially immunotherapy and specific targeted therapy, can cause uveitis, but it is not fully understood whether the clinical features of this drug-induced uveitis differ from those of other types of uveitis and whether there are differences between these drugs. We retrospectively reviewed the published cases and case series in PubMed, Embase, Web of Science, and Cochrane from January 2011 to October 2020. We analysed the data, including patients’ basic information, medications used, duration of use, time to onset, clinical manifestations, diagnosis, treatment, and prognosis of uveitis. We focused on the differences in uveitis caused by immunotherapy and specific targeted therapy. Altogether 93 cases (43 men, 48 women, and 2 cases whose gender was not mentioned) reported in 55 articles were included in this study. The average age was 59.6 ± 13.5 years. Eighty percent of the patients had bilateral involvement. Sixty cases were caused by immunotherapy (64.5%), and twenty-six were caused by specific targeted therapy (27.9%). No significant difference was found in the mean time from treatment to onset between the two groups. Anticancer drug-induced uveitis can involve all parts of the uvea from anterior to posterior, manifested as anterior chamber flare, anterior chamber cells, papillitis, macular oedema, subretinal fluid, and choroidal effusion. Anterior uveitis (24 cases, 40.0%) was more common in immunotherapy, and intermediate uveitis (8 cases, 30.8%) was more common in specific targeted therapy. The mean LogMAR visual acuity in specific targeted therapy at presentation was lower than in immunotherapy, but it was not statistically significant. Corticosteroid therapy can effectively control uveitis induced by anticancer drugs. However, the survival prognosis was poor. Among the 19 patients with reported cancer prognosis, seven (36.8%) had no cancer progression, eight (42.1%) had further metastases, and four (21.0%) died of cancer. In conclusion, uveitis caused by anticancer drugs involves both eyes and manifests as various types of uveitis. Patients with specific targeted therapy are more likely to have intermediate uveitis and low vision, and immunotherapy patients are more likely to have anterior uveitis. Corticosteroids are effective against uveitis caused by anticancer drugs.
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Revenko A, Carnevalli LS, Sinclair C, Johnson B, Peter A, Taylor M, Hettrick L, Chapman M, Klein S, Solanki A, Gattis D, Watt A, Hughes AM, Magiera L, Kar G, Ireland L, Mele DA, Sah V, Singh M, Walton J, Mairesse M, King M, Edbrooke M, Lyne P, Barry ST, Fawell S, Goldberg FW, MacLeod AR. Direct targeting of FOXP3 in Tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer. J Immunother Cancer 2022; 10:jitc-2021-003892. [PMID: 35387780 PMCID: PMC8987763 DOI: 10.1136/jitc-2021-003892] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited in high frequencies to the tumor microenvironment where they can suppress antitumor immunity. We hypothesized that pharmacological inhibition of FOXP3 by systemically delivered, unformulated constrained ethyl-modified antisense oligonucleotides could modulate the activity of Tregs and augment antitumor immunity providing therapeutic benefit in cancer models and potentially in man. METHODS We have identified murine Foxp3 antisense oligonucleotides (ASOs) and clinical candidate human FOXP3 ASO AZD8701. Pharmacology and biological effects of FOXP3 inhibitors on Treg function and antitumor immunity were tested in cultured Tregs and mouse syngeneic tumor models. Experiments were controlled by vehicle and non-targeting control ASO groups as well as by use of multiple independent FOXP3 ASOs. Statistical significance of biological effects was evaluated by one or two-way analysis of variance with multiple comparisons. RESULTS AZD8701 demonstrated a dose-dependent knockdown of FOXP3 in primary Tregs, reduction of suppressive function and efficient target downregulation in humanized mice at clinically relevant doses. Surrogate murine FOXP3 ASO, which efficiently downregulated Foxp3 messenger RNA and protein levels in primary Tregs, reduced Treg suppressive function in immune suppression assays in vitro. FOXP3 ASO promoted more than 70% reduction in FOXP3 levels in Tregs in vitro and in vivo, strongly modulated Treg effector molecules (eg, ICOS, CTLA-4, CD25 and 4-1BB), and augmented CD8+ T cell activation and produced antitumor activity in syngeneic tumor models. The combination of FOXP3 ASOs with immune checkpoint blockade further enhanced antitumor efficacy. CONCLUSIONS Antisense inhibitors of FOXP3 offer a promising novel cancer immunotherapy approach. AZD8701 is being developed clinically as a first-in-class FOXP3 inhibitor for the treatment of cancer currently in Ph1a/b clinical trial (NCT04504669).
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Affiliation(s)
| | | | | | - Ben Johnson
- Ionis Pharmaceuticals, Carlsbad, California, USA
| | | | | | | | - Melissa Chapman
- Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | | | | | | | - Andrew Watt
- Ionis Pharmaceuticals, Carlsbad, California, USA
| | | | | | - Gozde Kar
- Oncology R&D, AstraZeneca, Cambridge, UK
| | | | | | - Vasu Sah
- Oncology R&D, AstraZeneca, Waltham, MA, USA
| | | | | | | | | | | | - Paul Lyne
- Oncology R&D, AstraZeneca, Waltham, MA, USA
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Jung M, Kang M, Kim BS, Hong J, Kim C, Koh CH, Choi G, Chung Y, Kim BS. Nanovesicle-Mediated Targeted Delivery of Immune Checkpoint Blockades to Potentiate Therapeutic Efficacy and Prevent Side Effects. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2106516. [PMID: 34962660 DOI: 10.1002/adma.202106516] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/22/2021] [Indexed: 06/14/2023]
Abstract
Despite the clinically proven efficacies of immune checkpoint blockades, including anti-cytotoxic T lymphocyte-associated protein 4 antibody (αCTLA-4), the low response rate and immune-related adverse events (irAEs) in cancer patients represent major drawbacks of the therapy. These drawbacks of αCTLA-4 therapy are mainly due to the suboptimal activation of tumor-specific cytotoxic T lymphocytes (CTLs) and the systemic nonspecific activation of T cells. To overcome such drawbacks, αCTLA-4 is delivered by dendritic cell-derived nanovesicles presenting tumor antigens (DCNV-TAs) that exclusively interact with tumor-specific T cells, leading to selective activation of tumor-specific CTLs. Compared to conventional αCTLA-4 therapy, treatment with αCTLA-4-conjugated DCNV-TAs significantly inhibits tumor growth and reduces irAEs in syngeneic tumor-bearing mice. This study demonstrates that the spatiotemporal presentation of both αCTLA-4 and tumor antigens enables selective activation of tumor-specific T cells and potentiates the antitumor efficacy of αCTLA-4 without inducing systemic irAEs.
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Affiliation(s)
- Mungyo Jung
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Mikyung Kang
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Seok Kim
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Jihye Hong
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Cheesue Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Choong-Hyun Koh
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Garam Choi
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Soo Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
- Institute of Chemical Processes, Institute of Engineering Research, and BioMAX, Seoul National University, Seoul, 08826, Republic of Korea
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11
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Tang L, Wang J, Lin N, Zhou Y, He W, Liu J, Ma X. Immune Checkpoint Inhibitor-Associated Colitis: From Mechanism to Management. Front Immunol 2021; 12:800879. [PMID: 34992611 PMCID: PMC8724248 DOI: 10.3389/fimmu.2021.800879] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 11/29/2021] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs), as one of the innovative types of immunotherapies, including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors, have obtained unprecedented benefit in multiple malignancies. However, the immune response activation in the body organs could arise immune-related adverse events (irAEs). Checkpoint inhibitor colitis (CIC) is the most widely reported irAEs. However, some obscure problems, such as the mechanism concerning gut microbiota, the confusing differential diagnosis with inflammatory bowel disease (IBD), the optimal steroid schedule, the reintroduction of ICIs, and the controversial prognosis features, influence the deep understanding and precise diagnosis and management of CIC. Herein, we based on these problems and comprehensively summarized the relevant studies of CIC in patients with NSCLC, further discussing the future research direction of this specific pattern of irAEs.
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Affiliation(s)
- Liansha Tang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jialing Wang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Nan Lin
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwen Zhou
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Wenbo He
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jiyan Liu
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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12
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Belmontes B, Sawant DV, Zhong W, Tan H, Kaul A, Aeffner F, O'Brien SA, Chun M, Noubade R, Eng J, Ma H, Muenz M, Li P, Alba BM, Thomas M, Cook K, Wang X, DeVoss J, Egen JG, Nolan-Stevaux O. Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell-cold solid tumors. Sci Transl Med 2021; 13:13/608/eabd1524. [PMID: 34433637 DOI: 10.1126/scitranslmed.abd1524] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 07/28/2021] [Indexed: 12/15/2022]
Abstract
Therapeutic approaches are needed to promote T cell-mediated destruction of poorly immunogenic, "cold" tumors typically associated with minimal response to immune checkpoint blockade (ICB) therapy. Bispecific T cell engager (BiTE) molecules induce redirected lysis of cancer cells by polyclonal T cells and have demonstrated promising clinical activity against solid tumors in some patients. However, little is understood about the key factors that govern clinical responses to these therapies. Using an immunocompetent mouse model expressing a humanized CD3ε chain (huCD3e mice) and BiTE molecules directed against mouse CD19, mouse CLDN18.2, or human EPCAM antigens, we investigated the pharmacokinetic and pharmacodynamic parameters and immune correlates associated with BiTE efficacy across multiple syngeneic solid-tumor models. These studies demonstrated that pretreatment tumor-associated T cell density is a critical determinant of response to BiTE therapy, identified CD8+ T cells as important targets and mediators of BiTE activity, and revealed an antagonistic role for CD4+ T cells in BiTE efficacy. We also identified therapeutic combinations, including ICB and 4-1BB agonism, that synergized with BiTE treatment in poorly T cell-infiltrated, immunotherapy-refractory tumors. In these models, BiTE efficacy was dependent on local expansion of tumor-associated CD8+ T cells, rather than their recruitment from circulation. Our findings highlight the relative contributions of baseline T cell infiltration, local T cell proliferation, and peripheral T cell trafficking for BiTE molecule-mediated efficacy, identify combination strategies capable of overcoming resistance to BiTE therapy, and have clinical relevance for the development of BiTE and other T cell engager therapies.
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Affiliation(s)
- Brian Belmontes
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, Thousand Oaks, CA 91320, USA
| | - Deepali V Sawant
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA
| | - Wendy Zhong
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA
| | - Hong Tan
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, Thousand Oaks, CA 91320, USA
| | - Anupurna Kaul
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA
| | - Famke Aeffner
- Amgen Research, Thousand Oaks, CA 91320, USA.,Translational Safety and Bioanalytical Sciences, Amgen, South San Francisco, CA 94080, USA
| | - Sarah A O'Brien
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA
| | - Matthew Chun
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA
| | - Rajkumar Noubade
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA
| | - Jason Eng
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA
| | - Hayley Ma
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, Thousand Oaks, CA 91320, USA
| | - Markus Muenz
- Amgen Research, Thousand Oaks, CA 91320, USA.,Amgen Research GmbH, Munich 81477, Germany
| | - Peng Li
- Amgen Research, Thousand Oaks, CA 91320, USA.,Therapeutic Discovery, Amgen, South San Francisco, CA 94080, USA
| | - Benjamin M Alba
- Amgen Research, Thousand Oaks, CA 91320, USA.,Therapeutic Discovery, Amgen, South San Francisco, CA 94080, USA
| | - Melissa Thomas
- Amgen Research, Thousand Oaks, CA 91320, USA.,Therapeutic Discovery, Amgen, South San Francisco, CA 94080, USA
| | - Kevin Cook
- Amgen Research, Thousand Oaks, CA 91320, USA.,Pharmacokinetics and Drug Metabolism, Amgen, South San Francisco, CA 94080, USA
| | - Xiaoting Wang
- Amgen Research, Thousand Oaks, CA 91320, USA.,Translational Safety and Bioanalytical Sciences, Amgen, South San Francisco, CA 94080, USA
| | - Jason DeVoss
- Amgen Research, Thousand Oaks, CA 91320, USA.,Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA
| | - Jackson G Egen
- Amgen Research, Thousand Oaks, CA 91320, USA. .,Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA
| | - Olivier Nolan-Stevaux
- Amgen Research, Thousand Oaks, CA 91320, USA. .,Inflammation and Oncology Therapeutic Area, Amgen, South San Francisco, CA 94080, USA
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13
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Quach HT, Johnson DB, LeBoeuf NR, Zwerner JP, Dewan AK. Cutaneous adverse events caused by immune checkpoint inhibitors. J Am Acad Dermatol 2021; 85:956-966. [PMID: 34332798 DOI: 10.1016/j.jaad.2020.09.054] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 11/25/2022]
Abstract
IMPORTANCE Immune checkpoint inhibitors (ICIs) have emerged as active therapies for a variety of cancers. Cutaneous toxicities are common immune-related adverse events and patients will often be referred to dermatologists for evaluation. OBSERVATIONS Cutaneous adverse events to ICIs can have a variety of clinical presentations. Among the more common are eczematous, morbilliform, and lichenoid dermatoses, as well as vitiligo and pruritus. Less common adverse events include psoriasiform dermatoses, bullous disorders, and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Because of the immunologic mechanism of ICIs, there are also a variety of rheumatologic adverse reactions with cutaneous manifestations, such as scleroderma, dermatomyositis, cutaneous lupus erythematosus, and various vasculitides. These cutaneous reactions often respond to topical or systemic steroids, although specific toxicities may have alternative treatments available. CONCLUSIONS AND RELEVANCE As they become more widely prescribed, dermatologists will see an increasing number of patients with cutaneous adverse events caused by ICI therapies. Accurately diagnosing and treating these toxicities is paramount to achieving the most favorable outcomes for patients.
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Affiliation(s)
- Henry T Quach
- Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Douglas B Johnson
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
| | - Nicole R LeBoeuf
- Department of Dermatology, The Center for Cutaneous Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts
| | - Jeffrey P Zwerner
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Anna K Dewan
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee.
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14
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Retinal toxicities of systemic anticancer drugs. Surv Ophthalmol 2021; 67:97-148. [PMID: 34048859 DOI: 10.1016/j.survophthal.2021.05.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 05/08/2021] [Accepted: 05/10/2021] [Indexed: 01/07/2023]
Abstract
Newer anticancer drugs have revolutionized cancer treatment in the last decade, but conventional chemotherapy still occupies a central position in many cancers, with combination therapy and newer methods of delivery increasing their efficacy while minimizing toxicities. We discuss the retinal toxicities of anticancer drugs with an emphasis on the mechanism of toxicity. Uveitis is seen with the use of v-raf murine sarcoma viral oncogene homolog B editing anticancer inhibitors as well as immunotherapy. Most of the cases are mild with only anterior uveitis, but severe cases of posterior uveitis, panuveitis, and Vogt-Koyanagi-Harada-like disease may also occur. In the retina, a transient neurosensory detachment is observed in almost all patients on mitogen-activated protein kinase kinase (MEK) inhibitors. Microvasculopathy is often seen with interferon α, but vascular occlusion is a more serious toxicity caused by interferon α and MEK inhibitors. Crystalline retinopathy with or without macular edema may occur with tamoxifen; however, even asymptomatic patients may develop cavitatory spaces seen on optical coherence tomography. A unique macular edema with angiographic silence is characteristic of taxanes. Delayed dark adaptation has been observed with fenretinide. Interestingly, this drug is finding potential application in Stargardt disease and age-related macular degeneration.
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15
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Chhabra N, Kennedy J. A Review of Cancer Immunotherapy Toxicity: Immune Checkpoint Inhibitors. J Med Toxicol 2021; 17:411-424. [PMID: 33826117 DOI: 10.1007/s13181-021-00833-8] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 02/08/2021] [Accepted: 02/16/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer immunotherapy, which leverages features of the immune system to target neoplastic cells, has revolutionized the treatment of cancer. The use of these therapies has rapidly expanded in the past two decades. Immune checkpoint inhibitors represent one drug class within immunotherapy with its first agent FDA-approved in 2011. Immune checkpoint inhibitors act by disrupting inhibitory signals from neoplastic cells to immune effector cells, allowing activated T-cells to target these neoplastic cells. Unique adverse effects associated with immune checkpoint inhibitors are termed immune-related adverse effects (irAEs) and are usually immunostimulatory in nature. Almost all organ systems may be affected by irAEs including the dermatologic, gastrointestinal, pulmonary, endocrine, and cardiovascular systems. These effects range from mild to life-threatening, and their onset can be delayed several weeks or months. For mild irAEs, symptomatic care is usually sufficient. For higher grade irAEs, discontinuation of therapy and initiation of immunosuppressive therapy may be necessary. The management of patients with irAEs involves multidisciplinary care coordination with respect to the long-term goals the individual patient. Clinicians must be aware of the unique and sometimes fatal toxicologic profiles associated with immunotherapies to ensure prompt diagnosis and appropriate management.
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Affiliation(s)
- Neeraj Chhabra
- Cook County Health, Department of Emergency Medicine, Division of Medical Toxicology, 1950 W Polk Street, 7th Floor, Chicago, IL, 60612, USA. .,Toxikon Consortium, Chicago, IL, USA.
| | - Joseph Kennedy
- Cook County Health, Department of Emergency Medicine, Division of Medical Toxicology, 1950 W Polk Street, 7th Floor, Chicago, IL, 60612, USA.,Toxikon Consortium, Chicago, IL, USA
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16
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Wang S, Sun Z, Hou Y. Engineering Nanoparticles toward the Modulation of Emerging Cancer Immunotherapy. Adv Healthc Mater 2021; 10:e2000845. [PMID: 32790039 DOI: 10.1002/adhm.202000845] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/09/2020] [Indexed: 12/16/2022]
Abstract
Cancer immunotherapy is a new therapeutic strategy to fight cancer by activating the patients' own immune system. At present, immunotherapy approaches such as cancer vaccines, immune checkpoint blockade (ICB), adoptive cell transfer (ACT), monoclonal antibodies (mAbs) therapy, and cytokines therapy have therapeutic potential in preclinical and clinical applications. However, the intrinsic limitations of conventional immunotherapy are difficulty of precise dosage control, insufficient enrichment in tumor tissues, partial immune response silencing or hyperactivity, and high cost. Engineering nanoparticles (NPs) have been emerging as a promising multifunctional platform to enhance conventional immunotherapy due to their intrinsic immunogenicity, convenient delivery function, controlled surface chemistry activity, multifunctional modifying potential, and intelligent targeting. This review presents the recent progress reflected by engineering NPs, including the diversified selection of functionalized NPs, the superiority of engineering NPs for enhancing conventional immunotherapy, and NP-mediated multiscale strategies for synergistic therapy consisting of compositions and their mechanism. Finally, the perspective on multifunctional NP-based cancer immunotherapy for boosting immunomodulation is discussed, which reveals the expanding landscape of engineering NPs in clinical translation.
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Affiliation(s)
- Shuren Wang
- Beijing Key Laboratory of Magnetoelectric Materials and Devices Department of Materials Science and Engineering College of Engineering Beijing Innovation Centre for Engineering Science and Advanced Technology Peking University Beijing 100871 China
| | - Zhaoli Sun
- Beijing Key Laboratory of Magnetoelectric Materials and Devices Department of Materials Science and Engineering College of Engineering Beijing Innovation Centre for Engineering Science and Advanced Technology Peking University Beijing 100871 China
- College of Life Sciences Peking University Beijing 100871 China
| | - Yanglong Hou
- Beijing Key Laboratory of Magnetoelectric Materials and Devices Department of Materials Science and Engineering College of Engineering Beijing Innovation Centre for Engineering Science and Advanced Technology Peking University Beijing 100871 China
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17
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Biewenga M, van der Kooij MK, Wouters MWJM, Aarts MJB, van den Berkmortel FWPJ, de Groot JWB, Boers-Sonderen MJ, Hospers GAP, Piersma D, van Rijn RS, Suijkerbuijk KPM, Ten Tije AJ, van der Veldt AAM, Vreugdenhil G, Haanen JBAG, van der Eertwegh AJM, van Hoek B, Kapiteijn E. Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients. Hepatol Int 2021; 15:510-519. [PMID: 33634373 PMCID: PMC8144142 DOI: 10.1007/s12072-021-10151-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/25/2021] [Indexed: 12/17/2022]
Abstract
Background Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort. Methods Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3–4 hepatitis and outcome. Results 2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44). Conclusion Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome. Supplementary Information The online version contains supplementary material available at 10.1007/s12072-021-10151-4.
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Affiliation(s)
- Maaike Biewenga
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | | | - Michel W J M Wouters
- Department of Medical and Surgical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.,Scientific Bureau, Dutch Institute for Clinical Auditing, Leiden, The Netherlands
| | - Maureen J B Aarts
- Department of Medical Oncology, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | | | | | - Marye J Boers-Sonderen
- Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Geke A P Hospers
- Department of Medical Oncology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Djura Piersma
- Department of Internal Medicine, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Rozemarijn S van Rijn
- Department of Internal Medicine, Medical Centre Leeuwarden, Leeuwarden, The Netherlands
| | | | - Albert J Ten Tije
- Department of Internal Medicine, Amphia Hospital, Breda, The Netherlands
| | - Astrid A M van der Veldt
- Departments of Medical Oncology and Radiology and Nuclear Medicine, Erasmus Medical Centre Cancer Institute, Rotterdam, The Netherlands
| | - Gerard Vreugdenhil
- Department of Internal Medicine, Maxima Medical Centre, Eindhoven/Veldhoven, The Netherlands
| | - John B A G Haanen
- Department of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | - Alfons J M van der Eertwegh
- Department of Medical Oncology, Cancer Centre Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Ellen Kapiteijn
- Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands.
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18
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Salinas N, Nowak E, Etienne M, Legoupil D, Fouchard M, Brenaut E, Misery L. Causes of Pruritus in Patients Treated With Immune Checkpoint Inhibitors for Melanomas or Skin Carcinomas. Front Med (Lausanne) 2021; 8:632683. [PMID: 33634154 PMCID: PMC7900003 DOI: 10.3389/fmed.2021.632683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 01/12/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Pruritus is a frequent adverse event during the use of immune checkpoint inhibitors (ICIs), with a frequency estimated to be between 11 and 47%. The underlying causes remain poorly understood. Objectives: The main goal was to search for putative causes of pruritus occurring in patients treated with ICIs for melanomas and cutaneous carcinomas. Other objectives were to assess the association between the occurrence of pruritus and survival and between the occurrence of pruritus and other adverse events. Methods: A monocentric retrospective descriptive study was performed using data for patients treated with ICIs (nivolumab, pembrolizumab, ipilimumab, and cemiplimab) between August 2010 and November 2019. Results: A total of 181 patients were included (mean age: 69 years). Pruritus was reported by 25 patients (13.8%). We were able to determine three subgroups of pruritus causes under ICI use: pruritus directly related to immunotherapy, pruritus indirectly related through other pruritus-inducing side effects and pruritus unrelated to ICIs. In 6/25 patients, no more specific cause of pruritus was found at the onset of pruritus or in their backgrounds, other than ICI use. Limitations: The study has some limitations due to unicentric and retrospective design. Conclusion: Pruritus was found in 25/181 patients in this series; only in 6/25 patients no potential cause other than ICI could be found, and pruritus was not associated with differences in survival.
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Affiliation(s)
- Nadia Salinas
- Department of Dermatology, University Hospital of Brest, Brest, France.,Université de Brest, LIEN, Brest, France
| | - Emmanuel Nowak
- INSERM CIC 1412, University Hospital of Brest, Brest, France
| | - Maxime Etienne
- Department of Dermatology, University Hospital of Brest, Brest, France.,Université de Brest, LIEN, Brest, France
| | - Delphine Legoupil
- Department of Dermatology, University Hospital of Brest, Brest, France.,Université de Brest, LIEN, Brest, France
| | - Maxime Fouchard
- Department of Dermatology, University Hospital of Brest, Brest, France.,Université de Brest, LIEN, Brest, France
| | - Emilie Brenaut
- Department of Dermatology, University Hospital of Brest, Brest, France.,Université de Brest, LIEN, Brest, France
| | - Laurent Misery
- Department of Dermatology, University Hospital of Brest, Brest, France.,Université de Brest, LIEN, Brest, France
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19
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Skin Reactions to Immune Checkpoint Inhibitors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1342:319-330. [DOI: 10.1007/978-3-030-79308-1_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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20
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Regev A, Avigan MI, Kiazand A, Vierling JM, Lewis JH, Omokaro SO, Di Bisceglie AM, Fontana RJ, Bonkovsky HL, Freston JW, Uetrecht JP, Miller ED, Pehlivanov ND, Haque SA, Harrison MJ, Kullak-Ublick GA, Li H, Patel NN, Patwardhan M, Price KD, Watkins PB, Chalasani NP. Best practices for detection, assessment and management of suspected immune-mediated liver injury caused by immune checkpoint inhibitors during drug development. J Autoimmun 2020; 114:102514. [DOI: 10.1016/j.jaut.2020.102514] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 07/07/2020] [Indexed: 02/07/2023]
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21
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Tolstrup LK, Bastholt L, Dieperink KB, Möller S, Zwisler AD, Pappot H. The use of patient-reported outcomes to detect adverse events in metastatic melanoma patients receiving immunotherapy: a randomized controlled pilot trial. J Patient Rep Outcomes 2020; 4:88. [PMID: 33125537 PMCID: PMC7599285 DOI: 10.1186/s41687-020-00255-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 10/11/2020] [Indexed: 02/06/2023] Open
Abstract
Background A randomized controlled pilot trial was conducted to assess if melanoma patients treated with immunotherapy had the number of grade 3 or 4 adverse events during treatment reduced by 50% using a tailored electronic patient-reported outcomes tool in addition to standard toxicity monitoring compared to standard monitoring alone. Secondary endpoints were: if more AEs were reported in the intervention group, if there was a difference between the two groups in the number of telephone consultations, extra out-patient visits, number of days in the hospital, days in steroid treatment and the time patients experienced grade 2 or higher toxicity. Patients and methods Melanoma patients receiving immunotherapy at the Department of Oncology, Odense University Hospital, Denmark participated. Standard care included assessment of AEs by a clinician before each treatment cycle using the Common Terminology Criteria for Adverse Events. In addition, patients randomized to the intervention reported their AEs weekly by an electronic PRO-tool based on the PRO-CTCAE platform. Results One hundred forty-six melanoma patients were randomized. In this study, we did not detect a difference between the two groups in the number of grade 3 or 4 AEs (P = 0.983), in the overall number of AEs (P = 0.560) or in the time the patients in the two groups experienced grade 2 or higher toxicity (0.516). The number of phone contacts was significantly higher in the intervention group (P = 0.009) and there was a tendency towards patients in the intervention group having more extra visits (P = 0.156). Conclusion It has been examined if the number of severe AEs for melanoma patients receiving immunotherapy could be reduced by involving the patients in the reporting of symptoms. The results do not justify the expansion of the pilot study into a regular phase III study with this particular set-up. However, a significant difference in the number of phone contacts was found as patients in the intervention group called more frequently, indicating that their attention to AEs was increased. Even though the use of an electronic PRO tool could not reduce the number of severe AEs in this melanoma population, a positive impact on other endpoints such as QoL, communication, or treatment-planning, cannot be excluded. Trial registration Clinicaltrials.gov NCT03073031 Registered 8 March 2017, Retrospectively registered.
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Affiliation(s)
- Lærke K Tolstrup
- Department of Oncology, Odense University Hospital, Odense, Denmark. .,Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
| | - Lars Bastholt
- Department of Oncology, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Karin B Dieperink
- Department of Oncology, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Sören Möller
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,OPEN - Open Patient data Explorative Network, Odense University Hospital, Odense, Denmark
| | - Ann-Dorthe Zwisler
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,The Danish Knowledge Centre for Rehabilitation and Palliative Care (REHPA), Nyborg, Denmark
| | - Helle Pappot
- Department of Oncology, Copenhagen University Hospital, Copenhagen, Denmark
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22
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Critical Care Management of Toxicities Associated With Targeted Agents and Immunotherapies for Cancer. Crit Care Med 2020; 48:10-21. [PMID: 31725440 DOI: 10.1097/ccm.0000000000004087] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES To describe the most common serious adverse effects and organ toxicities associated with emerging therapies for cancer that may necessitate admission to the ICU. DATA SOURCES AND STUDY SELECTION PubMed and Medline search of relevant articles in English on the management of adverse effects of immunotherapy for cancer. DATA EXTRACTION AND DATA SYNTHESIS Targeted therapies including tyrosine kinase inhibitors, monoclonal antibodies, checkpoint inhibitors, and immune effector cell therapy have improved the outcome and quality of life of patients with cancer. However, severe and life-threatening side effects can occur. These toxicities include infusion or hypersensitivity reactions, cytokine release syndrome, pulmonary, cardiac, renal, hepatic, and neurologic toxicities, hemophagocytic lymphohistiocytosis, opportunistic infections, and endocrinopathies. Cytokine release syndrome is the most common serious toxicity after administration of monoclonal antibodies and immune effector cell therapies. Most of the adverse events from immunotherapy results from an exaggerated T-cell response directed against normal tissue, resulting in the generation of high levels of proinflammatory cytokines. Toxicities from targeted therapies are usually secondary to "on target toxicities." Management is largely supportive and may include discontinuation of the specific agent, corticosteroids, and other immune suppressing agents for severe (grade 3 or 4) immune-related adverse events like neurotoxicity and pneumonitis. CONCLUSIONS The complexity of toxicities associated with modern targeted and immunotherapeutic agents for cancer require a multidisciplinary approach among ICU staff, oncologists, and organ specialists and adoption of standardized treatment protocols to ensure the best possible patient outcomes.
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Abstract
Immune checkpoint inhibitors (ICIs) have shown significant benefit in cancer patients. Their success, however, is associated with immune-related adverse events (irAEs), which commonly affect the gastrointestinal tract, resulting in diarrhea and colitis. IrAEs range from mild self-limiting to severe life-threatening diseases and potentially limit the use of these medications. Diagnosis of ICI-induced enterocolitis is based on clinical symptoms, physical examination, stool tests, endoscopic and histologic evaluation, and/or imaging. Current management strategy is mainly anti-diarrheal agents for mild symptoms and immunosuppressants (e.g., corticosteroids, and infliximab or vedolizumab) for more severe diseases.
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Wayant C, Bindernagel R, Vassar M. TIDieR checklist evaluation of clinical trial intervention reporting for recent FDA-approved anticancer medications. BMJ Evid Based Med 2020; 25:97-101. [PMID: 31653687 DOI: 10.1136/bmjebm-2019-111249] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/15/2019] [Indexed: 11/04/2022]
Abstract
IMPORTANCE Clear and comprehensive descriptions of clinical trial interventions are necessary to translate new results into clinical practice. The TIDieR checklist was developed to be a minimum set of key items considered essential to high-quality reporting of clinical trial interventions. OBJECTIVE To determine the quality of reporting of recent Food and Drug Administration (FDA)-approved oncology interventions. DESIGN Cross-sectional investigation. SETTING/PARTICIPANTS/INTERVENTION Recent, FDA-approved haematology/oncology anticancer interventions. MAIN OUTCOME MEASURE Quality of reporting. RESULTS Across all included trials (n=96), a median of 8-9 (out of 12) TIDieR items were reported. Seven TIDieR items had >90% adherence, including individual-level and study-level modifications of drugs and dosing schedules. Three items were less often reported: intervention provider, including training and expertise (7/192, 3.6%); trial institution infrastructure (0/192, 0.0%); and how intervention compliance was assessed (59/192, 30.7%). Publication of a protocol improved intervention reporting (p<0.001). CONCLUSIONS In this analysis of clinical trials of recent, FDA-approved anticancer interventions, we found good adherence to the TIDieR checklist. These studies were homogeneous in their structure and included information; some TIDieR items were always or never/rarely reported. Clinical trial effect sizes may not translate to real-world practice for a number of reasons. Thus, to aid the translation of trial effect sizes to real-world practice, we recommend authors adhere to the TIDieR checklist and describe the infrastructure of trial centres and describe who provided the intervention, along with their expertise.
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Affiliation(s)
- Cole Wayant
- Psychiatry and Behavioral Sciences, Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma, USA
| | - Richard Bindernagel
- Kansas City University of Medicine and Biosciences, Kansas City, Missouri, USA
| | - Matt Vassar
- Psychiatry and Behavioral Sciences, Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma, USA
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Yaşar HA, Akkus E, Heper A, Akay BN, Urun Y, Utkan G. Sweet's syndrome under ipilimumab therapy and a brief comparison of the cases in literature. J Oncol Pharm Pract 2020; 26:1762-1764. [PMID: 32089071 DOI: 10.1177/1078155220906885] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Ipilimumab is an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody. Ipilimumab has shown improvement in overall survival in patients with advanced melanoma. Because ipilimumab activates the immune system against the tumor, ipilimumab is associated with adverse events related to immune system activation. Immune-associated side effects are frequently seen in the gastrointestinal system and skin. Sweet's syndrome (SS) is an uncommon inflammatory disorder. Some drugs or malignancy can cause SS. Only a few case reports have been reported of ipilimumab-associated SS. CASE A 53-year-old female with metastatic melanoma was treated with ipilimumab. After the fourth cycle, she developed painful lesions on her legs and hands. The pathologic biopsy of the lesions revealed neutrophilic dermatosis consistent with SS.Management and outcome: The patient was treated with 60 mg/day of prednisone for four days, nonsteroidal anti-inflammatory drugs and inhaler bronchodilator and steroid. She had symptomatic relief at the beginning of treatment. The prednisone doses were quickly tapered every three days. When the patient was treated with 10 mg/day of prednisone for three days, the skin nodules recurred. Prednisone 40 mg per day was re-started and then a slower taper by decreasing by 10 mg/day every week was instituted. After one-month treatment the prednisone dose was given as a 5 mg doses for one week and then stopped. No new lesions recurred after slower taper of prednisone. CONCLUSION Herein we report a case presented with SS under ipilimumab therapy. Melanoma patients treated with ipilimumab can develop SS. The clinicians should be aware of this condition.
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Affiliation(s)
- Hatime A Yaşar
- Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey
| | - Erman Akkus
- Department of Internal Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Aylin Heper
- Department of Pathology, Ankara University School of Medicine, Ankara, Turkey
| | - Bengu N Akay
- Department of Dermatology, Ankara University School of Medicine, Ankara, Turkey
| | - Yuksel Urun
- Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey
| | - Gungor Utkan
- Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey
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Abstract
There is an urgent need for improved cancer immunotherapies. The nanoparticles described here deliver genes to stimulate the immune system to specifically kill tumor cells. This synthetic, biodegradable system avoids the use of common gene delivery materials like viruses that can have safety concerns and manufacturing limitations. Local nanoparticle delivery evades adverse side effects stemming from systemic administration of immune-activating therapeutics. Importantly, this technology causes a tumor-targeting response but does not require prior knowledge of a particular patient’s gene expression profile; thus, it can serve as a platform to combat many different solid cancers. Moreover, local nanoparticle administration causes a systemic cellular immune response, which has the potential to lead to better outcomes in the context of recurrence or metastasis. Cancer immunotherapy has been the subject of extensive research, but highly effective and broadly applicable methods remain elusive. Moreover, a general approach to engender endogenous patient-specific cellular therapy, without the need for a priori knowledge of tumor antigen, ex vivo cellular manipulation, or cellular manufacture, could dramatically reduce costs and broaden accessibility. Here, we describe a biotechnology based on synthetic, biodegradable nanoparticles that can genetically reprogram cancer cells and their microenvironment in situ so that the cancer cells can act as tumor-associated antigen-presenting cells (tAPCs) by inducing coexpression of a costimulatory molecule (4-1BBL) and immunostimulatory cytokine (IL-12). In B16-F10 melanoma and MC38 colorectal carcinoma mouse models, reprogramming nanoparticles in combination with checkpoint blockade significantly reduced tumor growth over time and, in some cases, cleared the tumor, leading to long-term survivors that were then resistant to the formation of new tumors upon rechallenge at a distant site. In vitro and in vivo analyses confirmed that locally delivered tAPC-reprogramming nanoparticles led to a significant cell-mediated cytotoxic immune response with systemic effects. The systemic tumor-specific and cell-mediated immunotherapy response was achieved without requiring a priori knowledge of tumor-expressed antigens and reflects the translational potential of this nanomedicine.
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Skin Reactions to Immune Checkpoint Inhibitors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1244:235-246. [DOI: 10.1007/978-3-030-41008-7_11] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Thalambedu N, Khan Y, Zhang Q, Khanal S, Ashfaq A. Immune-mediated Colitis from Dual Checkpoint Inhibitors. Cureus 2019; 11:e6233. [PMID: 31890432 PMCID: PMC6935326 DOI: 10.7759/cureus.6233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Melanoma is a deadly disease with immunotherapy treatment options that emerged in the last few years and have changed the disease outcome. However, it is associated with immune-related toxic effects despite improving survival. We present the case of a 53-year-old woman who had two weeks of diarrhea after she was treated with dual immunotherapy agents for her advanced melanoma. The final workup revealed pancolitis, possibly due to immunotherapy adverse effects. Initial conservative treatment, unfortunately, did not lead to a clinical improvement until a steroid was introduced. We are reporting this case to alert our fellow physicians about the immune-mediated toxicities of the relatively new checkpoint inhibitors.
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Affiliation(s)
| | - Yasir Khan
- Internal Medicine, Abington Hospital - Jefferson Health, Abington, USA
| | - Qian Zhang
- Internal Medicine, Abington Hospital, Jefferson Health, Abington, USA
| | - Shristi Khanal
- Internal Medicine, Abington Hospital-Jefferson Health, Abington, USA
| | - Ammar Ashfaq
- Internal Medicine, Abington Hospital-Jefferson Health, Abington, USA
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The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis. J Immunother 2019; 41:101-108. [PMID: 29401166 DOI: 10.1097/cji.0000000000000213] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Checkpoint inhibitors are a first-line therapy for advanced melanoma, though their use is limited by diarrhea and colitis. The aim of our study was to determine the risk of these toxicities associated with immunotherapy in advanced melanoma. Electronic databases were searched through June 2017 for prospective studies reporting the risk of diarrhea and colitis in advanced melanoma treated with anti-programmed death-1 (PD-1) or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors. Standardized definitions assessed the grade of diarrhea and colitis. Pooled incidence and weighted relative risk estimates with 95% confidence intervals (CI) were estimated using random effects model. Eighteen studies were included: 6 studies (1537 patients) with PD-1 inhibitors and 15 studies (3116 patients) with CTLA-4 inhibitors. The incidence of all-grade diarrhea was 13.7% (95% CI, 10.1%-17.2%) for anti-PD-1 and 35.4% (95% CI, 30.4%-40.5%) for anti-CTLA-4. The incidence of all-grade colitis was 1.6% (95% CI, 0.7%-2.4%) for anti-PD-1, and 8.8% (95% CI, 6.1%-11.5%) for anti-CTLA-4. When PD-1 inhibitors were compared directly with CTLA-4 inhibitors, the relative risk of all-grade diarrhea was 0.58 (95% CI, 0.43-0.77), and the relative risk of all-grade colitis was 0.16 (95% CI, 0.05-0.51). The rate of therapy discontinuation was numerically higher for anti-CTLA-4 therapy compared with anti-PD-1 therapy. Finally, 2 studies compared combination immunotherapy with anti-CTLA-4 therapy alone. The relative risk of developing all-grade diarrhea and colitis with combination therapy was 1.31 (95% CI, 1.09-1.57) and 1.21 (95% CI, 0.73-1.99), respectively. Diarrhea and colitis are frequent toxicities associated with checkpoint inhibitors, and seem to be most common with CTLA-4 inhibitors.
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Ihara K. Immune checkpoint inhibitor therapy for pediatric cancers: A mini review of endocrine adverse events. Clin Pediatr Endocrinol 2019; 28:59-68. [PMID: 31384097 PMCID: PMC6646237 DOI: 10.1297/cpe.28.59] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 03/15/2019] [Indexed: 12/27/2022] Open
Abstract
In recent years, immune checkpoint inhibitor therapy has attracted a great deal of attention in the field of cancer treatment. In the clinical setting, antibodies targeting programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have been successfully used to treat adult patients with various types of intractable cancer. However, in a substantial number of patients, ICI therapy is associated with autoimmune toxicities known as immune-related adverse events (IRAEs). Endocrinopathies, such as hypophysitis or autoimmune thyroid disease, may occur and can present unique clinical features that have not been documented with traditional chemotherapies. A Japanese clinical trial evaluating the anti-PD-1 antibody nivolumab for the treatment of pediatric patients with refractory malignant solid tumors and Hodgkin lymphoma has been ongoing since 2017. Moreover, tumors associated with Lynch syndrome, a hereditary form of mismatch repair deficiency, are being focused and represent the next target for ICI therapy in Japan. For the safe management of pediatric cancer patients treated with ICIs, pediatric endocrinologists must be aware of the risk of autoimmune endocrinopathies and perform relevant screening tests at appropriate stages of growth and development.
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Affiliation(s)
- Kenji Ihara
- Department of Pediatrics, Oita University Faculty of Medicine, Yufu, Japan
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31
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Macroangiopathy is a positive predictive factor for response to immunotherapy. Sci Rep 2019; 9:9728. [PMID: 31278360 PMCID: PMC6611819 DOI: 10.1038/s41598-019-46189-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 06/18/2019] [Indexed: 01/01/2023] Open
Abstract
Immunotherapies demand for predictive biomarkers to avoid unnecessary adverse effects and costs. Analytic morphomics is the technique to use body composition measures as imaging biomarkers for underlying pathophysiology to predict prognosis or outcome to therapy. We investigated different body composition measures to predict response to immunotherapy. This IRB approved retrospective analysis encompassed 147 patients with ipilimumab therapy. Degree of macroangiopathy was quantified with the newly defined total plaque index (TPI), i.e. the body height corrected sum of the soft and hard plaque volume of the infrarenal aorta on portalvenous CT scans. Furthermore, mean psoas density (MPD), different adipose tissue parameters as well as degree of cerebral microangiopathy were extracted from the imaging data. Subsequent multivariate Cox regression analysis encompassed TPI, MPD, serum LDH, S100B, age, gender, number of immunotherapy cycles as well as extent of distant metastases. TPI and MPD correlated positively with PFS in multivariate analysis (p = 0.03 and p = 0.001, respectively). Furthermore, single visceral organ and/or soft tissue involvement significantly decreased progression risk (p = 0.01), whereas increased S100B level showed a trend towards PFS shortening (p = 0.05). In conclusion, degree of macroangiopathy and sarcopenia were independent predictors for outcome to immunotherapy and of equivalent significance compared to other clinical biomarkers.
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Simsek M, Bilici M, Tekin SB. Creatinine kinase elevation and peripheral neuropathy during nivolumab treatment of a patient with metastatic renal cell carcinoma. Indian J Cancer 2019; 55:413-414. [PMID: 30829281 DOI: 10.4103/ijc.ijc_151_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
We report elevation of creatinine kinase (CK), which is an uncommon adverse event related to treatment with nivolumab. Nivolumab is a monoclonal antibody against programmed cell death-1 and an effective agent in metastatic renal cell carcinoma (RCCa). Here, we report a case of 58 year-old male receiving nivolumab as fourth-line treatment for metastatic RCCa. The patient was admitted to our clinic with pelvic pain and weakness in his legs. Elevated CK level was noted and he was hospitalized. About 1 mg/kg methylprednisolone was initiated and nivolumab was discontinued. On the second day of his hospitalization, left facial palsy occurred. After his neuropathy improved and CK level normalized, the patient was discharged. Neurological immune-related adverse events are very rare with nivolumab but can be serious.
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Affiliation(s)
- Melih Simsek
- Department of Medical Oncology, Ataturk University Faculty of Medicine, Erzurum, Turkey
| | - Mehmet Bilici
- Department of Medical Oncology, Ataturk University Faculty of Medicine, Erzurum, Turkey
| | - Salim Basol Tekin
- Department of Medical Oncology, Ataturk University Faculty of Medicine, Erzurum, Turkey
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33
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Sekiya T, Takaki S. RGMB enhances the suppressive activity of the monomeric secreted form of CTLA-4. Sci Rep 2019; 9:6984. [PMID: 31061392 PMCID: PMC6502797 DOI: 10.1038/s41598-019-43068-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 03/15/2019] [Indexed: 12/17/2022] Open
Abstract
The immunoregulatory molecule CTLA-4 plays a crucial role in the maintenance of immune homeostasis. CTLA-4-neutralizing antibodies are now approved for the treatment of advanced melanoma, and are in development for treating other cancers as well. However, a thorough understanding of CTLA-4 function at the molecular level is necessary in order to develop strategies to prevent the unintended autoimmunity that is frequently associated with systemic blockade of CTLA-4 activity. Here, we describe an extracellular molecule, repulsive guidance molecule B (RGMB) as a novel binding partner of CTLA-4. RGMB expression was detected at high levels in dendritic cell subsets that have been suggested to have tolerogenic capabilities. RGMB binds an extracellular domain of CTLA-4, and specifically strengthens the binding of the monomeric, soluble form of CTLA-4 (sCTLA-4) to CD80, enhancing CTLA-4's suppressive effect on co-stimulation. Examination of expression data from tumor tissues revealed a negative correlation between RGMB expression and immune activation status in the majority of non-hematologic tumor tissues. These findings advance our understanding of CTLA-4 activity, as well as identify the RGMB/CTLA-4 binding interface as a potential target for the development of novel immune checkpoint blockade therapies.
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Affiliation(s)
- Takashi Sekiya
- Section of Immune Response Modification, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
- Department of Immune Regulation, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
| | - Satoshi Takaki
- Department of Immune Regulation, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
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Mir-Bonafé J, Saceda-Corralo D, Vañó-Galván S. Adverse Hair Reactions to New Targeted Therapies for Cancer. ACTAS DERMO-SIFILIOGRAFICAS 2019. [DOI: 10.1016/j.adengl.2019.02.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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35
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Mir-Bonafé J, Saceda-Corralo D, Vañó-Galván S. Reacciones capilares de las nuevas terapias diana dirigidas contra el cáncer. ACTAS DERMO-SIFILIOGRAFICAS 2019; 110:182-192. [DOI: 10.1016/j.ad.2018.10.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 09/27/2018] [Accepted: 10/13/2018] [Indexed: 12/16/2022] Open
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Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia S, Budde LE, Costa L, Davies M, Dunnington D, Ernstoff MS, Frigault M, Hoffner B, Hoimes CJ, Lacouture M, Locke F, Lunning M, Mohindra NA, Naidoo J, Olszanski AJ, Oluwole O, Patel SP, Reddy S, Ryder M, Santomasso B, Shofer S, Sosman JA, Wahidi M, Wang Y, Johnson-Chilla A, Scavone JL. Management of Immunotherapy-Related Toxicities, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2019; 17:255-289. [DOI: 10.6004/jnccn.2019.0013] [Citation(s) in RCA: 376] [Impact Index Per Article: 62.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visitNCCN.org.
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Affiliation(s)
- John A. Thompson
- 1Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | - Julie Brahmer
- 3The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | - Shailender Bhatia
- 1Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | - Luciano Costa
- 7University of Alabama at Birmingham Comprehensive Cancer Center
| | | | | | | | | | | | - Christopher J. Hoimes
- 13Case Comprehensive Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | | | - Nisha A. Mohindra
- 16Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - Jarushka Naidoo
- 3The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | | | | | | | | | | | - Jeffrey A. Sosman
- 16Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | - Yinghong Wang
- 23The University of Texas MD Anderson Cancer Center; and
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Hodgson A, Almansouri Z, Adeyi O, Fischer SE. Gross and microscopic changes of liver neoplasms and background hepatic structures following neoadjuvant therapy. J Clin Pathol 2019; 72:112-119. [PMID: 30670563 DOI: 10.1136/jclinpath-2018-205596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Accepted: 11/26/2018] [Indexed: 01/03/2023]
Abstract
Liver transplantation is a surgical option with curative intent used in the management of some cases of hepatocellular carcinoma and cholangiocarcinoma (hilar, rarely intrahepatic). A number of different therapeutic modalities including ablative techniques, arterially directed therapies, radiation and chemotherapy are used in the neoadjuvant setting prior to liver transplantation with the goals of preventing tumour progression, decreasing post-transplant recurrence and possibly downstaging patients with tumour burden beyond what is acceptable by current transplant criteria. Pathologists evaluating hepatic explants must be aware of these neoadjuvant therapies and the alterations induced by them in both tumourous and non-tumourous tissue. In this review, we discuss common neoadjuvant therapies used in in this setting, as well as the gross and microscopic changes induced by these presurgical treatments within hepatic neoplasms as well as the background hepatic parenchyma and nearby structures. Select secondary tumours involving the liver which are pretreated will also be discussed. Finally, proper reporting of these changes will be mentioned.
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Affiliation(s)
- Anjelica Hodgson
- Department of Pathobiology and Laboratory Medicine, The University of Toronto, Toronto, Ontario, Canada.,Department of Pathology, University Health Network, Toronto, Ontario, Canada
| | - Zuhoor Almansouri
- Department of Pathobiology and Laboratory Medicine, The University of Toronto, Toronto, Ontario, Canada.,Department of Pathology, University Health Network, Toronto, Ontario, Canada
| | - Oyedele Adeyi
- Department of Pathobiology and Laboratory Medicine, The University of Toronto, Toronto, Ontario, Canada.,Department of Pathology, University Health Network, Toronto, Ontario, Canada
| | - Sandra E Fischer
- Department of Pathobiology and Laboratory Medicine, The University of Toronto, Toronto, Ontario, Canada .,Department of Pathology, University Health Network, Toronto, Ontario, Canada
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Cervantes J, Rosen A, Dehesa L, Dickinson G, Alonso-Llamazares J. Granulomatous Reaction in a Patient With Metastatic Melanoma Treated With Ipilimumab: First Case Reported With Isolated Cutaneous Findings. ACTAS DERMO-SIFILIOGRAFICAS 2019. [DOI: 10.1016/j.adengl.2018.11.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Basile D, Lisanti C, Pizzichetta MA, Baldo P, Fornasier G, Lo Re F, Corona G, Puglisi F. Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Cutaneous Melanoma. Recent Pat Anticancer Drug Discov 2019; 14:203-225. [PMID: 31362664 DOI: 10.2174/1574892814666190726130351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 07/19/2019] [Accepted: 07/23/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND Malignant melanoma is a skin cancer responsible for 90% of cutaneous cancer- related deaths. In recent years, breakthroughs in treatment strategy have revolutionized the prognosis in both early and advanced melanoma patients. In particular, treatment with monoclonal antibodies targeting co-inhibitory checkpoints or specific molecular pathways leads to a new era of promising options, by prolonging the survival time of these patients. Moreover, unlike the chemotherapy that was used until some time ago, these new drugs have a good and more manageable toxicity profile. However, because of the recent introduction in clinical practice of the new agents, there is a learning curve among physicians regarding early recognition and management of the associated side effects. OBJECTIVES The analysis of the toxicity profiles of the different agents currently studied for the treatment of early and advanced melanoma, and the description of several relevant recent patents in this field, are the aims of this review. METHODS This is a systematically conducted review based on current clinical guidelines and on international Pharmacovigilance databases (AERS-Eudravigilance - WHO Vigibase). RESULTS Our systematic analysis outlines a comprehensive overview of the pharmacology, clinical application and the safety of recent anticancer drugs to treat melanoma, which can be an essential instrument for health professionals and researchers. CONCLUSION The new oncological therapies against melanoma are based on increasingly specific biological and immunological targets. For this reason, the potential toxicities that are expected from patients would be less relevant than the systemic "classical" chemotherapy. However, the new therapies are not free from the risk of causing adverse reactions, some of which must be managed promptly and appropriately; moreover, the multiplicity of the metabolic pathways exposes the new target therapies to relevant potential interactions. This review can help to understand how important it is not to underestimate potential adverse drug reactions related to new targeted therapies.
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Affiliation(s)
- Debora Basile
- Department of Medicine, University of Udine, Udine 33100, Italy
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano 33081, Italy
| | - Camilla Lisanti
- Department of Medicine, University of Udine, Udine 33100, Italy
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano 33081, Italy
| | - Maria A Pizzichetta
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano 33081, Italy
- Dermatologic Clinic, University of Trieste, Trieste, Italy
| | - Paolo Baldo
- Pharmacy Unit, Centro di Riferimento Oncologico di Aviano 33081 (CRO), IRCCS, Aviano, Italy
| | - Giulia Fornasier
- Pharmacy Unit, Centro di Riferimento Oncologico di Aviano 33081 (CRO), IRCCS, Aviano, Italy
| | - Francesco Lo Re
- Pharmacy Unit, Centro di Riferimento Oncologico di Aviano 33081 (CRO), IRCCS, Aviano, Italy
| | - Giuseppe Corona
- Department of Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano 33081, Italy
| | - Fabio Puglisi
- Department of Medicine, University of Udine, Udine 33100, Italy
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano 33081, Italy
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Cervantes J, Rosen A, Dehesa L, Dickinson G, Alonso-Llamazares J. Reacción granulomatosa en paciente con melanoma metastásico tratado con ipilimumab: primer caso descrito presentando clínica cutánea únicamente. ACTAS DERMO-SIFILIOGRAFICAS 2019; 110:43-49. [DOI: 10.1016/j.ad.2017.11.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 11/24/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
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Ahmed M. Checkpoint inhibitors: What gastroenterologists need to know. World J Gastroenterol 2018; 24:5433-5438. [PMID: 30622372 PMCID: PMC6319137 DOI: 10.3748/wjg.v24.i48.5433] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/07/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
Checkpoint inhibitors are increasingly being used in clinical practice. They can cause various gastrointestinal, hepatic and pancreatic side effects. As these side effects can be serious, appropriate management is essential. The different checkpoint inhibitors with their mechanisms of action and indications, as well as evaluation and management of gastrointestinal, hepatic and pancreatic side effects, are discussed in this article.
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Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
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Majenka P, Hoffmann M, Rötzer I, Dimitrakopoulou-Strauss A, Koschny R, Longerich T, Enk A, Hassel JC. Diet-dependent toxicity of ipilimumab in metastatic melanoma. Eur J Cancer 2018; 106:220-224. [PMID: 30528806 DOI: 10.1016/j.ejca.2018.10.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 10/03/2018] [Accepted: 10/27/2018] [Indexed: 11/25/2022]
Affiliation(s)
- P Majenka
- Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
| | - M Hoffmann
- Department of Nutrition Therapy, National Center for Tumor Diseases, Heidelberg, Germany
| | - I Rötzer
- Department of Nutrition Therapy, National Center for Tumor Diseases, Heidelberg, Germany
| | - A Dimitrakopoulou-Strauss
- Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - R Koschny
- Department of Gastroenterology, Infection and Intoxication, University Hospital Heidelberg, Heidelberg, Germany
| | - T Longerich
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - A Enk
- Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - J C Hassel
- Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
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43
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Zhang B, Wu Q, Zhou YL, Guo X, Ge J, Fu J. Immune-related adverse events from combination immunotherapy in cancer patients: A comprehensive meta-analysis of randomized controlled trials. Int Immunopharmacol 2018; 63:292-298. [PMID: 30130720 DOI: 10.1016/j.intimp.2018.08.014] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/30/2018] [Accepted: 08/13/2018] [Indexed: 01/03/2023]
Abstract
BACKGROUND Although available evidence from clinical trials has shown that immune checkpoint inhibitors (ICIs) combination therapy can lead to a series of immune-related adverse events (irAEs), the overall risk of irAEs on combination therapy has yet not been systematically reported. Therefore, we performed a meta-analysis to comprehensively explore the overall risks for irAEs on combination immunotherapy. METHODS PubMed, Embase, and Google Scholar were systematically searched for relevant randomized controlled trials (RCTs) comparing combination immunotherapy to monotherapy. The meta-analysis was conducted by using Review Manager 5.3. RESULTS A total of 11 RCTs involving 5307 patients were eligible for this meta-analysis. The risk ratio for all-grade diarrhea and all-grade colitis for combination therapy was 1.95 (95% CI 1.54, 2.46; P < 0.00001) and 4.45 (95% CI 3.04, 6.51; P < 0.00001), respectively. The risk ratio for all-grade hyperthyroidism and all-grade hypothyroidism for combination therapy was 2.84 (95% CI 1.71, 4.72; P < 0.0001) and 1.71 (95% CI 1.38, 2.13; P < 0.00001), respectively. The risk ratio for all-grade increased AST and all-grade increased ALT was 3.87 (95% CI 2.74, 5.47; P < 0.00001) and 4.29 (95% CI 3.05, 6.04; P < 0.00001), respectively. The risk ratio for all-grade hypophysitis and all-grade pneumonitis was 4.24 (95% CI 2.26, 7.98; P < 0.00001) and 2.92 (95% CI 1.60, 5.33; P = 0.0005), respectively. CONCLUSIONS Patients receiving combination immunotherapy are at increased risk of selected all-grade irAEs. Although fatal high-grade irAEs is rare, AEs caused by combination immunotherapy should be recognized promptly in order to avoid more serious complications.
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Affiliation(s)
- Bo Zhang
- Medical School of Nantong University, 19 Qixiu Road, Nantong 260001, Jiangsu, PR China
| | - Qiong Wu
- Medical School of Nantong University, 19 Qixiu Road, Nantong 260001, Jiangsu, PR China
| | - You Lang Zhou
- The Hand Surgery Research Center, Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong 226001, PR China.
| | - Xinyu Guo
- Medical School of Nantong University, 19 Qixiu Road, Nantong 260001, Jiangsu, PR China
| | - Jun Ge
- Medical School of Nantong University, 19 Qixiu Road, Nantong 260001, Jiangsu, PR China
| | - Jiaji Fu
- Medical School of Nantong University, 19 Qixiu Road, Nantong 260001, Jiangsu, PR China
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Suzman DL, Pelosof L, Rosenberg A, Avigan MI. Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents. Liver Int 2018; 38:976-987. [PMID: 29603856 DOI: 10.1111/liv.13746] [Citation(s) in RCA: 157] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 03/21/2018] [Indexed: 12/13/2022]
Abstract
Immune checkpoint inhibitors (ICIs) block CTLA-4, PD-1 and PD-L1, or other molecules that control antitumour activities of lymphocytes. These products are associated with a broad array of immune-related toxicities affecting a variety of organs, including the liver. ICI-associated immune-mediated hepatitis (IMH) ranges in severity between mild and life-threatening and is marked by findings that bear both similarities as well as differences with idiopathic autoimmune hepatitis. Hepatotoxic events are often detected in clinical trials of ICIs that are powered for efficacy. Risk levels for ICI-induced liver injury may be impacted by the specific checkpoint molecule targeted for treatment, the ICI dose levels, and the presence of a pre-existing autoimmune diathesis, chronic infection or tumour cells which infiltrate the liver parenchyma. When patients develop liver injury during ICI treatment, a prompt assessment of the cause of injury, in conjunction with the application of measures to optimally manage the adverse event, should be made. Strategies to manage the risk of IMH include the performance of pretreatment liver tests with regular monitoring during and after ICI treatment and patient education. Using Common Terminology Criteria for Adverse Events developed at the National Cancer Institute to measure the severity level of liver injury, recommended actions may include continued ICI treatment with close patient monitoring, ICI treatment suspension or discontinuation and/or administration of corticosteroids or, when necessary, a non-steroidal immunosuppressive agent. The elucidation of reliable predictors of tumour-specific ICI treatment responses, as well as an increased susceptibility for clinically serious immune-related adverse events, would help optimize treatment decisions for individual patients.
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Affiliation(s)
- Daniel L Suzman
- Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Lorraine Pelosof
- Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Amy Rosenberg
- Office of Biotechnology Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Mark I Avigan
- Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
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45
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Long-term and late treatment consequences: endocrine and metabolic effects. Curr Opin Support Palliat Care 2018; 11:205-213. [PMID: 28661901 DOI: 10.1097/spc.0000000000000289] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE OF REVIEW Cancer therapies often result in the 'late effect of cancer treatment' whereby secondary health complications emerge years after radiotherapy and chemotherapy. This review focuses on endocrine and metabolic consequences in adult cancer survivors as late treatment effects. RECENT FINDINGS Endocrine and metabolic disorders are among the most common late effects. Endocrine disorders include hypopituitarism, which leads to growth hormone deficiency, hypogonadism, adrenal insufficiency and hypothyroidism and related clinical manifestations. Hypogonadism in particular is associated with a wide range of health complications requiring input from the like of endocrine and fertility specialists. Immune checkpoint inhibitors are novel anticancer agents, some of which are uniquely associated with hypophysitis which requires early recognition and management, including steroid replacement. Metabolic syndrome, a significant risk for cardiovascular disease, is highly prevalent. Although the effects of cranial irradiation on the hypothalamic-pituitary system are more apparent, the relationship between chemotherapy and endocrine/metabolic disorders remains to be elucidated. There exist published guidelines for monitoring endocrine and cardiometabolic risk in cancer survivors, but the extent of monitoring appears insufficient. SUMMARY Regular monitoring and early management of endocrine/metabolic disorders is required to prevent the elevated rates of health complications after cancer treatment, and thereby improve cancer survivorship.
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46
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Knochelmann HM, Dwyer CJ, Bailey SR, Amaya SM, Elston DM, Mazza-McCrann JM, Paulos CM. When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell Mol Immunol 2018; 15:458-469. [PMID: 29563615 PMCID: PMC6068176 DOI: 10.1038/s41423-018-0004-4] [Citation(s) in RCA: 372] [Impact Index Per Article: 53.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 01/08/2018] [Accepted: 01/09/2018] [Indexed: 12/24/2022] Open
Abstract
The balance between Th17 cells and regulatory T cells (Tregs) has emerged as a prominent factor in regulating autoimmunity and cancer. Th17 cells are vital for host defense against pathogens but have also been implicated in causing autoimmune disorders and cancer, though their role in carcinogenesis is less well understood. Tregs are required for self-tolerance and defense against autoimmunity and often correlate with cancer progression. This review addresses the importance of a functional homeostasis between these two subsets in health and the consequences of its disruption when these forces collide in disease. Importantly, we discuss the ability of Th17 cells to mediate cancer regression in immunotherapy, including adoptive transfer and checkpoint blockade therapy, and the therapeutic possibilities of purposefully offsetting the Th17/Treg balance to treat patients with cancer as well as those with autoimmune diseases.
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Affiliation(s)
- Hannah M Knochelmann
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
- Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, USA.
| | - Connor J Dwyer
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Stefanie R Bailey
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Sierra M Amaya
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Dirk M Elston
- Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Joni M Mazza-McCrann
- Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Chrystal M Paulos
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
- Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC, USA.
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Zaman A, Bivona TG. Emerging application of genomics-guided therapeutics in personalized lung cancer treatment. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:160. [PMID: 29911108 DOI: 10.21037/atm.2018.05.02] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In lung cancer, genomics-driven comprehensive molecular profiling has identified novel chemically and immunologically addressable vulnerabilities, resulting in an increasing application of precision medicine by targeted inactivation of tumor oncogenes and immunogenic activation of host anti-tumor surveillance as modes of treatment. However, initially profound response of these targeted therapies is followed by relapse due to therapy-resistant residual disease states. Although distinct mechanisms and frameworks for therapy resistance have been proposed, accounting for and upfront prediction of resistance trajectories has been challenging. In this review, we discuss in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the current standing, and challenges associated with genomics-guided strategies for personalized therapy against both oncogenic alterations as well as post-therapy resistance mechanisms. In NSCLC, we catalog the targeted therapy approaches against most notable oncogenic alterations such as epidermal growth factor receptor (EGFR), serine/threonine-protein kinase b-raf (BRAF), Kirsten rat sarcoma viral proto-oncogene (KRAS), anaplastic lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase (ROS1). For SCLC, currently highly recalcitrant to targeted therapy, we enumerate a range of exciting and maturing precision medicine approaches. Furthermore, we discuss a number of immunotherapy approaches, in combination or alone, that are being actively pursued clinically in lung cancer. This review not only highlights common mechanistic themes underpinning different classes of resistance and discusses tumor heterogeneity as a source of residual disease, but also discusses potential ways to overcome these barriers. We emphasize how an extensive understanding of these themes can predict and improve therapeutic strategies, such as through poly-therapy approaches, to forestall tumor evolution upfront.
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Affiliation(s)
- Aubhishek Zaman
- Department of Medicine, University of California, San Francisco, CA, USA.,UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Trever G Bivona
- Department of Medicine, University of California, San Francisco, CA, USA.,UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, USA
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Karamchandani DM, Chetty R. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective. J Clin Pathol 2018; 71:665-671. [PMID: 29703758 DOI: 10.1136/jclinpath-2018-205143] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 04/10/2018] [Indexed: 12/15/2022]
Abstract
Immune checkpoint inhibitors (CPIs) are a relatively new class of 'miracle' dugs that have revolutionised the treatment and prognosis of some advanced-stage malignancies, and have increased the survival rates significantly. This class of drugs includes cytotoxic T lymphocyte antigen-4 inhibitors such as ipilimumab; programmed cell death protein-1 inhibitors such as nivolumab, pembrolizumab and avelumab; and programmed cell death protein ligand-1 inhibitors such as atezolizumab. These drugs stimulate the immune system by blocking the coinhibitory receptors on the T cells and lead to antitumoural response. However, a flip side of these novel drugs is immune-related adverse events (irAEs), secondary to immune-mediated process due to disrupted self-tolerance. The irAEs in the gastrointestinal (GI) tract/liver may result in diarrhoea, colitis or hepatitis. An accurate diagnosis of CPI-induced colitis and/or hepatitis is essential for optimal patient management. As we anticipate greater use of these drugs in the future given the significant clinical response, pathologists need to be aware of the spectrum of histological findings that may be encountered in GI and/or liver biopsies received from these patients, as well as differentiate them from its histopathological mimics. This present review discusses the clinical features, detailed histopathological features, management and the differential diagnosis of the luminal GI and hepatic irAEs that may be encountered secondary to CPI therapy.
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Affiliation(s)
- Dipti M Karamchandani
- Division of Anatomic Pathology, Department of Pathology, Penn State Health Milton S Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Runjan Chetty
- Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
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Sosa A, Lopez Cadena E, Simon Olive C, Karachaliou N, Rosell R. Clinical assessment of immune-related adverse events. Ther Adv Med Oncol 2018; 10:1758835918764628. [PMID: 29623110 PMCID: PMC5882039 DOI: 10.1177/1758835918764628] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 02/15/2018] [Indexed: 12/18/2022] Open
Abstract
Immunotherapy through checkpoint inhibitors is now standard practice for a growing number of cancer types, supported by overall improvement of clinical outcomes and better tolerance. One anti-CTLA-4 antibody (ipilimumab), two anti-PD-1 antibodies (pembrolizumab and nivolumab) and three anti-PD-L1 antibodies (atezolizumab, avelumab and durvalumab) have been approved for clear benefits across diverse trials. Adverse events of an immune nature associated with these agents frequently affect the skin, colon, endocrine glands, lungs and liver. Most of these effects are mild and can be managed through transient immunosuppression with corticosteroids, but high-grade events often require hospitalization and specialized treatment. However, since immunotherapy is recent, physicians with clinical experience in the diagnosis and management of immune toxicities are frequently those who actively participated in trials, but many practicing oncologists are still not familiarized with the assessment of these events. This review focuses on the incidence, diagnostic assessment and recommended management of the most relevant immune-related adverse events.
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Affiliation(s)
- Aaron Sosa
- Department of Medical Oncology, Hospital Universitari Sagrat Cor, Viladomat 288, Barcelona 08029, Spain
| | - Esther Lopez Cadena
- Department of Pneumonology, Hospital Universitari Sagrat Cor, Barcelona, Spain
| | | | - Niki Karachaliou
- Department of Medical Oncology, Hospital Universitari Sagrat Cor, Barcelona, Spain
| | - Rafael Rosell
- Department of Medical Oncology, Dr Rosell Oncology Institute, Barcelona, Spain
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50
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Kähler KC, Hassel JC, Heinzerling L, Loquai C, Mössner R, Ugurel S, Zimmer L, Gutzmer R. Management of side effects of immune checkpoint blockade by anti-CTLA-4 and anti-PD-1 antibodies in metastatic melanoma. J Dtsch Dermatol Ges 2018; 14:662-81. [PMID: 27373241 DOI: 10.1111/ddg.13047] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
CTLA-4 and PD-1 are potential targets for tumor-induced downregulation of lymphocytic immune responses. Immune checkpoint-modifying monoclonal antibodies oppose these effects, inducing T cell-mediated immune responses to various tumors including melanoma. Both anti-CTLA-4 and anti-PD-1 antibodies modify the interaction between tumor, antigen-presenting cells, and T lymphocytes. With respect to overall survival, clinical studies have shown a major benefit for the anti-CTLA-4 antibody ipilimumab as well as the two anti-PD-1 antibodies nivolumab and pembrolizumab. Following approval of ipilimumab in 2011, the latter two achieved market authorization in the summer of 2015. Immune responses thus induced and enhanced inevitably entail autoimmune phenomena, affecting various organs to varying degrees. Knowledge of these side effects is crucial with regard to prevention and management by treating physicians. Typically occurring early on and presenting with pronounced and persistent diarrhea, colitis represents a major and severe side effect. Other immune-mediated disorders include dermatitis, hypophysitis, thyroiditis, hepatitis, iridocyclitis as well as other less common autoimmune phenomena. Early recognition and initiation of treatment can reduce risks and sequelae for patients. This review describes the mechanisms of action of immune checkpoint blockade as well as its clinical effects in metastatic melanoma, with a detailed focus on the spectrum of adverse events and their therapeutic management.
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Affiliation(s)
- Katharina C Kähler
- Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Jessica C Hassel
- Department of Dermatology, and National Cancer Center, University Hospital Heidelberg, Heidelberg, Germany
| | - Lucie Heinzerling
- Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
| | - Carmen Loquai
- Department of Dermatology, Medical Faculty, University of Mainz, Mainz, Germany
| | - Rotraut Mössner
- Department of Dermatology, Venereology, and Allergology, University Medicine Göttingen, Göttingen, Germany
| | - Selma Ugurel
- Department of Dermatology, Venereology and Allergology, University Hospital Essen, Essen, Germany
| | - Lisa Zimmer
- Department of Dermatology, Venereology and Allergology, University Hospital Essen, Essen, Germany
| | - Ralf Gutzmer
- Hanover Skin Cancer Center, Department of Dermatology, Venereology, and Allergology, Hanover Medical College, Hanover, Germany
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