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He T, Chen K, Zhou Q, Cai H, Yang H. Immune repertoire profiling in myasthenia gravis. Immunol Cell Biol 2024; 102:891-906. [PMID: 39396830 DOI: 10.1111/imcb.12825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 06/26/2024] [Accepted: 09/19/2024] [Indexed: 10/15/2024]
Abstract
Myasthenia gravis (MG) is the most frequent immune-mediated neurological disorder, characterized by fluctuating muscle weakness. Specific recognition of self-antigens by T-cell receptors (TCRs) and B-cell receptors (BCRs), coupled with T-B cell interactions, activates B cells to produce autoantibodies, which are critical for the initiation and perpetuation of MG. The immune repertoire comprises all functionally diverse T and B cells at a specific time point in an individual, reflecting the essence of immune selectivity. By sequencing the nucleotide sequences of TCRs and BCRs, it is possible to track individual T- and B-cell clones. This review delves into the generation of autoreactive TCRs and BCRs in MG and comprehensively examines the applications of immune repertoire sequencing in understanding disease pathogenesis, developing diagnostic and prognostic markers and informing targeted therapies. We also discuss the current limitations and future potential of this approach.
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MESH Headings
- Myasthenia Gravis/immunology
- Humans
- Receptors, Antigen, B-Cell/metabolism
- Receptors, Antigen, B-Cell/genetics
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/genetics
- B-Lymphocytes/immunology
- Autoantibodies/immunology
- Animals
- Autoantigens/immunology
- T-Lymphocytes/immunology
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Affiliation(s)
- Ting He
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Kangzhi Chen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Qian Zhou
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Haobing Cai
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Huan Yang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
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Fekete GL, Iantovics LB, Fekete JE, Fekete L. Disseminate Cutaneous Vasculitis Associated with Durvalumab Treatment-Case Report, Mini-Review on Cutaneous Side Effects of Immune Checkpoint Inhibitor Therapies with Machine Learning Perspectives. Life (Basel) 2024; 14:1062. [PMID: 39337847 PMCID: PMC11433022 DOI: 10.3390/life14091062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 08/12/2024] [Accepted: 08/17/2024] [Indexed: 09/30/2024] Open
Abstract
Durvalumab is an IgG1 monoclonal antibody that has efficacy in many advanced-stage cancers, especially in small-cell lung cancer. The efficacy of durvalumab can be enhanced by chemotherapy. Cutaneous side effects due to treatment with durvalumab are usually self-limiting and easily manageable. We present a clinical case of a female patient aged 61, with small-cell lung carcinoma in stage III B, cT3N2M, who developed a disseminated cutaneous vasculitis after seven months of durvalumab monotherapy, having previously been treated with polychemotherapy according to oncological protocols. To the best of our knowledge, based on a comprehensive search in leading databases, like Web of Science, Scopus, PubMed and some others, ours is the first published case of disseminated cutaneous vasculitis as a result of Durvalumab treatment. Anticancer immunotherapy targeting immune checkpoint inhibition (ICI) has transformed the treatment and evolution of patients with multiple varieties of hematologic cancers. In this context, the cutaneous side effects due to immune checkpoint inhibitor therapies are very few in the scientific literature. Based on this need, we have performed a mini-review of cutaneous side effects due to immune checkpoint inhibitor therapies that treat actual aspects in this sense. We also present some artificial intelligence challenges and future perspectives in the combination of human reasoning and reasoning based on Artificial Intelligence for study of the very rare Disseminate cutaneous vasculitis associated with Durvalumab treatment.
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Affiliation(s)
- Gyula Laszlo Fekete
- Department of Dermatology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Laszlo Barna Iantovics
- Department of Electrical Engineering and Information Technology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Júlia Edit Fekete
- National Institute of Public Health, Regional Center for Public Health, 540142 Targu Mures, Romania
| | - Laszlo Fekete
- CMI Dermamed Private Medical Office, 540530 Targu Mures, Romania
- Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania
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Takada H, Yamashita K, Osawa L, Komiyama Y, Muraoka M, Suzuki Y, Sato M, Kobayashi S, Yoshida T, Takano S, Maekawa S, Enomoto N. Significance of the autoantibody assay in predicting the development of immune-related adverse events in patients receiving atezolizumab plus bevacizumab combination therapy for unresectable hepatocellular carcinoma. Hepatol Res 2024; 54:162-173. [PMID: 37740643 DOI: 10.1111/hepr.13969] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/06/2023] [Accepted: 09/20/2023] [Indexed: 09/24/2023]
Abstract
AIM Atezolizumab plus bevacizumab (AB) combination therapy is the first-line treatment for unresectable hepatocellular carcinoma (u-HCC). The management of immune-related adverse events (irAEs) is an important issue associated with achieving a good therapeutic response in patients receiving AB therapy. However, few studies have reported irAE development in patients receiving AB therapy. This study focused on the association between irAE development and autoantibodies at baseline in patients receiving AB therapy. METHODS Sixty-one patients receiving AB therapy were enrolled. For autoantibodies, the following antibodies were tested before the start of AB therapy: antinuclear antibodies, rheumatoid factor (RF), anti-thyroglobulin antibodies, thyroid peroxidase antibodies, anti-thyroid stimulating hormone receptor antibodies, and acetylcholine receptor antibodies. A patient was considered to have pre-existing antibodies if any of the listed antibodies were present at baseline. RESULTS Ten patients (16%) developed irAEs during the observation period. The irAEs included liver injury, hypothyroidism, adrenal insufficiency, adrenocorticotropic hormone deficiency, and rhabdomyolysis. Patients with irAE (n = 10) were more likely to be positive for any autoantibody (hazard ratio [HR] 3.7, p = 0.047) and RF at baseline (HR 5.4, p = 0.035) and to achieve complete response (HR 5.8, p = 0.027) than those without. The presence of autoantibodies at baseline was an independent factor associated with irAE development. CONCLUSION In the real world, 16% of patients receiving AB therapy for u-HCC developed irAEs. Patients with autoantibodies at baseline are at high risk of developing irAEs and require cautious follow-up.
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Affiliation(s)
- Hitomi Takada
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Koji Yamashita
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Leona Osawa
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yasuyuki Komiyama
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Masaru Muraoka
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yuichiro Suzuki
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Mitsuaki Sato
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Shoji Kobayashi
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Takashi Yoshida
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Shinichi Takano
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Shinya Maekawa
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Nobuyuki Enomoto
- Gastroenterology and Hepatology Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
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Murray JC, Sivapalan L, Hummelink K, Balan A, White JR, Niknafs N, Rhymee L, Pereira G, Rao N, Weksler B, Bahary N, Phallen J, Leal A, Bartlett DL, Marrone KA, Naidoo J, Goel A, Levy B, Rosner S, Hann CL, Scott SC, Feliciano J, Lam VK, Ettinger DS, Li QK, Illei PB, Monkhorst K, Scharpf RB, Brahmer JR, Velculescu VE, Zaidi AH, Forde PM, Anagnostou V. Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer. Clin Cancer Res 2024; 30:389-403. [PMID: 37939140 PMCID: PMC10792359 DOI: 10.1158/1078-0432.ccr-23-1469] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/05/2023] [Accepted: 11/03/2023] [Indexed: 11/10/2023]
Abstract
PURPOSE Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). EXPERIMENTAL DESIGN We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. RESULTS Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. CONCLUSIONS Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.
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Affiliation(s)
- Joseph C. Murray
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Lung Cancer Precision Medicine Center of Excellence, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lavanya Sivapalan
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Karlijn Hummelink
- Antoni van Leeuwenhoek Nederlands Kanker Instituut, Amsterdam, the Netherlands
| | - Archana Balan
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - James R. White
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Noushin Niknafs
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lamia Rhymee
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Gavin Pereira
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nisha Rao
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Benny Weksler
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, Pennsylvania
| | - Nathan Bahary
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, Pennsylvania
| | - Jillian Phallen
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Alessandro Leal
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - David L. Bartlett
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, Pennsylvania
| | - Kristen A. Marrone
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Lung Cancer Precision Medicine Center of Excellence, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jarushka Naidoo
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Beaumont RCSI Cancer Centre, Dublin, Ireland
| | - Akul Goel
- California Institute of Technology, 1200 E California Blvd, Pasadena, California
| | - Benjamin Levy
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Samuel Rosner
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Christine L. Hann
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Susan C. Scott
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Josephine Feliciano
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Vincent K. Lam
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - David S. Ettinger
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Qing Kay Li
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - Peter B. Illei
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - Kim Monkhorst
- Antoni van Leeuwenhoek Nederlands Kanker Instituut, Amsterdam, the Netherlands
| | - Robert B. Scharpf
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Julie R. Brahmer
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Lung Cancer Precision Medicine Center of Excellence, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Victor E. Velculescu
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ali H. Zaidi
- Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, Pennsylvania
| | - Patrick M. Forde
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Valsamo Anagnostou
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Lung Cancer Precision Medicine Center of Excellence, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Gandarillas S, Newland ES, Toppmeyer D, Stephenson R, Denzin L, Dasgeb B. HLA inherence as a potential parameter in checkpoint inhibitor-associated autoimmune adverse event assessment. Front Med (Lausanne) 2024; 10:1288844. [PMID: 38259857 PMCID: PMC10800809 DOI: 10.3389/fmed.2023.1288844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
Background The success of immunotherapy has made it a lifesaving treatment, but not without side effects. Currently, the risk factors for developing immune-related adverse events (irAEs) in patients who receive immunotherapy are poorly understood, and there is no risk-stratifying mechanism for potentially fatal irAEs. It is postulated that oncology patients with preexisting autoimmune diseases are likely to have flares on immunotherapy. However, some patients develop de novo autoimmune conditions on immunotherapy without a prior history. Literature reports have postulated that human leukocyte antigen (HLA) inherence may play a role in irAEs. However, this potential remains underexplored. Methods The oncology patients who developed autoimmune adverse events on immunotherapy for whom the continuation of treatment was prudent or lifesaving were selected. Of note, all nine patients received checkpoint inhibitors (CIs). Of the nine selected patients, only one had a prior history of an autoimmune condition. None of the nine selected patients had an active autoimmune condition at the time of CI initiation. Their HLA was typed, and the results were cross-referenced with the literature reports in PubMed and Google search with the corresponding autoimmune condition of each patient. Results Herein, we report nine patients with irAEs for whom retrospective HLA typing revealed the inherence of multiple related HLA alleles that may correspond to the autoimmune condition that they had developed on immunotherapy. It is to be mentioned that the inherence of enriched disease-related HLA alleles was shared among patients with the same irAEs. These patients developed a range of irAEs including bullous pemphigoid, pemphigus foliaceus/vulgaris, thyroiditis, vitiligo, and hepatitis on immunotherapy. Although some combinations of disease-related HLA were well reported in otherwise idiopathic autoimmune diseases, a frequently repeated HLA allele combination in our patient population was found to be rarely seen in the general population. Conclusion The authors suggest that an enriched inherence of disease-related HLA alleles may play a role in the genetic propensity for the development of irAEs in oncology patients, who receive immunotherapy, including CIs. Inherence of more than one or a cluster of particular autoimmune disease-related HLA alleles in patients who receive immunotherapy may unmask the corresponding autoimmune disease as the genotype inherence presents with the phenotype of the corresponding condition. It is suggested that enriched linked HLA genotypes, which are otherwise rare in the general population, may present as the corresponding phenotype of the autoimmune condition. Such clinical presentation, enhanced by immunotherapy, such as CIs, can play a role in risk stratifying patients for precision medicine and improve the outcome.
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Affiliation(s)
- Sophia Gandarillas
- Department of Dermatology, Wayne State University, Detroit, MI, United States
| | | | - Deborah Toppmeyer
- Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
| | - Ryan Stephenson
- Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
| | - Lisa Denzin
- Department of Pediatrics, Child Health Institute of New Jersey, Rutgers Medical School, New Brunswick, NJ, United States
| | - Bahar Dasgeb
- Department of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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Murray JC, Sivapalan L, Hummelink K, Balan A, White JR, Niknafs N, Rhymee L, Pereira G, Rao N, Phallen J, Leal A, Bartlett DL, Marrone KA, Naidoo J, Levy B, Rosner S, Hann CL, Scott SC, Feliciano J, Lam VK, Ettinger DS, Li QK, Illei PB, Monkhorst K, Zaidi AH, Scharpf RB, Brahmer JR, Velculescu VE, Forde PM, Anagnostou V. Elucidating the heterogeneity of immunotherapy response and immune-related toxicities by longitudinal ctDNA and immune cell compartment tracking in lung cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.23.546338. [PMID: 37425893 PMCID: PMC10327039 DOI: 10.1101/2023.06.23.546338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Purpose Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect -especially in the setting of stable disease-call for the development of molecularly-informed real-time minimally invasive predictive biomarkers. In addition to capturing tumor regression, liquid biopsies may be informative in evaluating immune-related adverse events (irAEs). Experimental design We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response for each patient. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. Results Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank p=0.0003) and overall survival (log-rank p=0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions were noted on-treatment. Conclusions Molecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the tumor and immune compartments by liquid biopsies provides an approach for monitoring of clinical benefit and immune-related toxicities for patients with NSCLC receiving immunotherapy. Statement of translational relevance Longitudinal dynamic changes in cell-free tumor load and reshaping of the peripheral T-cell repertoire capture clinical outcomes and immune-related toxicities during immunotherapy for patients with non-small cell lung cancer.
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Zhou JM, Xiong HF, Chen XP, Zhang ZW, Zhu LP, Wu B. Correlation between immune-related adverse events and long-term outcomes in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: A retrospective study. World J Gastrointest Oncol 2023; 15:689-699. [PMID: 37123056 PMCID: PMC10134210 DOI: 10.4251/wjgo.v15.i4.689] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/16/2022] [Accepted: 03/23/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND Although immune checkpoint inhibitor (ICI) therapy has improved the prognosis of unresectable hepatocellular carcinoma (HCC), it has also resulted in unique immune-related adverse events (irAEs). The relationship between irAE and treatment outcomes in ICI-treated unresectable HCC patients remains unknown.
AIM To elucidate the correlation between immune-related toxic effects and prognosis in patients with unresectable HCC treated with pembrolizumab.
METHODS From March 2019 to February 2021, a total of 190 unresectable HCC (Barcelona Clinic Liver Cancer C) patients receiving pembrolizumab treatment were retrospectively reviewed. Overall survival (OS) was the primary endpoint, while objective response rate (ORR), disease control rate (DCR), and time to progression (TTP) were secondary evaluation indexes. We assessed demographics, irAEs, and outcomes by retrospective review.
RESULTS One hundred and forty-three males and 47 females were included in the study. The ORR and DCR were 12.1% (23/190) and 52.1% (99/190), respectively. The median OS was 376 d [95% confidence interval (CI): 340-411 d] and the median TTP was 98 d (95%CI: 75-124 d). The overall incidence of treatment-related adverse events was 72.6% (138/190) and 10.0% of them were severe irAEs (grade ≥ 3). Child-Pugh B class, portal vein tumor thrombus, extrahepatic metastasis, and hypothyroidism were the independent risk factors for survival. Patients with hypothyroidism showed a longer OS [517 d (95%CI: 423-562) vs 431 d (95%CI: 412-485), P = 0.011] and TTP [125 d (95%CI: 89-154) vs 87 d (95%CI: 61-98), P = 0.004] than those without irAEs.
CONCLUSION Pembrolizumab-treated patients with unresectable HCC who experienced hypothyroidism have promising ORR and durable response. Hypothyroidism, an irAE, may be used as a clinical evaluation parameter of response to ICIs in unresectable HCC.
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Affiliation(s)
- Jiang-Min Zhou
- Department of Hepatobiliary Surgery, Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan 430030, Hubei Province, China
| | - Hui-Fang Xiong
- Department of Digestive Medicine, Dongxihu District People’s Hospital, Wuhan 430030, Hubei Province, China
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zhi-Wei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Li-Ping Zhu
- Department of Hepatobiliary Surgery, Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan 430030, Hubei Province, China
| | - Biao Wu
- Department of Hepatobiliary Surgery, Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan 430030, Hubei Province, China
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Ao YQ, Gao J, Wang S, Jiang JH, Deng J, Wang HK, Xu B, Ding JY. Immunotherapy of thymic epithelial tumors: molecular understandings and clinical perspectives. Mol Cancer 2023; 22:70. [PMID: 37055838 PMCID: PMC10099901 DOI: 10.1186/s12943-023-01772-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 04/03/2023] [Indexed: 04/15/2023] Open
Abstract
Immunotherapy has emerged to play a rapidly expanding role in the treatment of cancers. Currently, many clinical trials of therapeutic agents are on ongoing with majority of immune checkpoint inhibitors (ICIs) especially programmed death receptor 1 (PD-1) and its ligand 1 (PD-L1) inhibitors. PD-1 and PD-L1, two main immune checkpoints, are expressed at high levels in thymic epithelial tumors (TETs) and could be predictors of the progression and immunotherapeutic efficacy of TETs. However, despite inspiring efficacy reported in clinical trials and clinical practice, significantly higher incidence of immune-related adverse events (irAEs) than other tumors bring challenges to the administration of ICIs in TETs. To develop safe and effective immunotherapeutic patterns in TETs, understanding the clinical properties of patients, the cellular and molecular mechanisms of immunotherapy and irAEs occurrence are crucial. In this review, the progress of both basic and clinical research on immune checkpoints in TETs, the evidence of therapeutic efficacy and irAEs based on PD-1 /PD-L1 inhibitors in TETs treatment are discussed. Additionally, we highlighted the possible mechanisms underlying irAEs, prevention and management strategies, the insufficiency of current research and some worthy research insights. High PD-1/PD-L1 expression in TETs provides a rationale for ICI use. Completed clinical trials have shown an encouraging efficacy of ICIs, despite the high rate of irAEs. A deeper mechanism understanding at molecular level how ICIs function in TETs and why irAEs occur will help maximize the immunotherapeutic efficacy while minimizing irAEs risks in TET treatment to improve patient prognosis.
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Affiliation(s)
- Yong-Qiang Ao
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Gao
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shuai Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia-Hao Jiang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Deng
- Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai, China
| | - Hai-Kun Wang
- CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Bei Xu
- Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Jian-Yong Ding
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China.
- Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
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Wilfong EM, Vowell KN, Crofford LJ, Kendall PL. Multiparameter analysis of human B lymphocytes identifies heterogeneous CD19 + CD21 lo subsets. Cytometry A 2023; 103:283-294. [PMID: 36281747 PMCID: PMC10085822 DOI: 10.1002/cyto.a.24699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/21/2022] [Accepted: 10/20/2022] [Indexed: 11/05/2022]
Abstract
Autoreactive B cell subsets have been described in a variety of settings, using multiple classification schemes and cell surface markers also found on healthy cells. CD19+ CD21lo B cells have been identified as an autoreactive-prone subset of B cells, although the downregulation of CD21 has been observed on a variety of B cell subsets in health and disease. This variation has led to confusion regarding the meaning and applicability of the loss or reduction of CD21 in peripheral B cells. To better understand the relationships between commonly used B cell markers and their associated characteristics, we analyzed human B cells from healthy participants using multiparameter flow cytometry and the visualization algorithm, tSNE. This approach revealed significant phenotypic overlap amongst five previously described autoimmune-prone B cell subsets, including CD19+ CD10- CD27- CD21lo B cells. Interestingly, 12 different subpopulations of CD19+ CD21lo B cells were identified, some of which mapped to previously described autoreactive populations, while others were consistent with healthy B cells. This suggests that CD21 is downregulated in a variety of circumstances involving B cell activation, all of which are present in low numbers even in healthy individuals. These findings describe the utility of unbiased multiparameter analysis using a relatively limited panel of flow cytometry markers to analyze autoreactive-prone and normal activated B cells.
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Affiliation(s)
- Erin M. Wilfong
- Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
- Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Katherine N. Vowell
- Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Leslie J. Crofford
- Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
- Department of Microbiology, Pathology and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - Peggy L. Kendall
- Division of Allergy, Pulmonary and Critical Care, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
- Department of Microbiology, Pathology and Immunology, Vanderbilt University Medical Center, Nashville, TN
- Division of Allergy/Immunology, Department of Medicine, Washington University, St. Louis, MO
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10
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Topp MS, Eradat H, Florschütz A, Hochhaus A, Wrobel T, Walewski J, Knopinska-Posluszny W, Kanate AS, Lech-Maranda E, Brunnberg U, Chitra S, Nielsen TG, Sellam G, Shivhare M, Lossos IS. Anti-CD20-atezolizumab-polatuzumab vedotin in relapsed/refractory follicular and diffuse large B-cell lymphoma. J Cancer Res Clin Oncol 2023; 149:811-817. [PMID: 35182224 PMCID: PMC9931830 DOI: 10.1007/s00432-021-03847-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 10/30/2021] [Indexed: 01/09/2023]
Abstract
PURPOSE New therapies are needed for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. This phase 1b, open-label trial evaluated two anti-CD20-based triplet combinations. METHODS Patients with R/R follicular lymphoma (FL; n = 13) were treated with obinutuzumab, atezolizumab, and polatuzumab vedotin (G-atezo-pola; 1.4 mg/kg/1.8 mg/kg) and patients with R/R diffuse large B-cell lymphoma (DLBCL; n = 23) received rituximab (R)-atezo-pola. The primary efficacy endpoint was complete response (CR) at end of induction (EOI) by PET-CT (investigator assessed; modified Lugano 2014 criteria). Safety endpoints were also assessed. RESULTS 13 FL patients were treated and evaluable for safety; 2/23 DLBCL patients did not receive treatment and were not included in the safety population. Median observation time was 23.3 and 5.7 months in the FL and DLBCL cohorts, respectively. At EOI, CR rates in FL patients treated with G-atezo-pola at pola doses of 1.4 mg/kg (N = 3) and 1.8 mg/kg (N = 7) were 33% and 14%, respectively. In DLBCL patients receiving R-atezo-pola, the CR rate at EOI was 13%. In the FL cohort, 62% of patients experienced a grade 3-5 adverse event (AE; including two deaths) and 31% developed a serious AE (SAE). In DLBCL patients, R-atezo-pola was associated with a lower incidence of grade 3-5 AEs (24%; one death) and SAEs (10%). In both cohorts, the most common grade 3-5 AEs were hematologic toxicities. CONCLUSION Based on these safety issues, considered as related specifically to G-atezo-pola, and limited efficacy, no further development of either combination is planned. TRIAL REGISTRATION NCT02729896; Date of registration: April 6, 2016.
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Affiliation(s)
- Max S Topp
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Anstalt des öffentlichen Rechts, Josef-Schneider-Straße 2, 97080, Würzburg, Germany.
| | - Herbert Eradat
- Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | | | - Andreas Hochhaus
- Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany
| | - Tomasz Wrobel
- Department of Hematology, Wrocław Medical University, Wrocław, Poland
| | - Jan Walewski
- Narodowy Instytut Onkologii im, Marii Skłodowskiej-Curie - Panstwowy Instytut Badawczy, Warsaw, Poland
| | | | | | - Ewa Lech-Maranda
- Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | | | | | | | - Gila Sellam
- F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | - Izidore S Lossos
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
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11
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Wu Y, Zhu W, Wang J, Liu L, Zhang W, Wang Y, Shi J, Xia J, Gu Y, Qian Q, Hong Y. Using machine learning for mortality prediction and risk stratification in atezolizumab-treated cancer patients: Integrative analysis of eight clinical trials. Cancer Med 2023; 12:3744-3757. [PMID: 35871390 PMCID: PMC9939114 DOI: 10.1002/cam4.5060] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/25/2022] [Accepted: 07/13/2022] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Few models exist to predict mortality in cancer patients receiving immunotherapy. Our aim was to build a machine learning-based risk stratification model for predicting mortality in atezolizumab-treated cancer patients. METHODS Data from 2538 patients in eight atezolizumab-treated cancer clinical trials across three cancer types (non-small-cell lung cancer, bladder transitional cell carcinoma, and renal cell carcinoma) were included. The whole cohort was randomly split into development and validation cohorts in a 7:3 ratio. Machine-learning algorithms (extreme gradient boosting, random forest, logistic regression with lasso regularization, support vector machine, and K-nearest neighbor) were applied to develop prediction models. Model performance was mainly assessed by area under the receiver operating characteristic curve (AUC) value, calibration plot, and decision curve analysis. The probability of death risk was then stratified. RESULTS One thousand and three hundred and seventy-nine (54.33%) patients died. The random forest (RF) model was overall the best in terms of predictive performance, with the AUC of 0.844 (95% confidence interval [CI]: 0.826-0.862) in the development cohort and 0.786 (95% CI: 0.754-0.818) in the validation cohort for predicting mortality. Twelve baseline variables contributing to mortality prediction in the RF model were C-reactive protein, PD-L1 level, cancer type, prior liver metastasis, derived neutrophil-to-lymphocyte ratio, alkaline phosphatase, albumin, hemoglobin, white blood cell count, number of metastatic sites, pulse rate, and Eastern Cooperative Oncology Group (ECOG) performance status. A total of 1782 (70.2%) patients were separated into the high-risk and 756 (29.8%) low-risk groups. Patients in the high-risk group were significantly more likely to die, experience disease progression, discontinue study, and discontinue treatment than patients in the low-risk group (all p values < 0.001). Risk groups were not associated with immune-related adverse events and grades 3-5 treatment-related adverse events (all p values > 0.05). CONCLUSION RF model has good performance in mortality prediction and risk stratification for cancer patients receiving atezolizumab monotherapy.
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Affiliation(s)
- Yougen Wu
- National Institute of Clinical Research, The Fifth People's Hospital of ShanghaiFudan UniversityShanghaiChina
| | - Wenyu Zhu
- Shanghai Long For Health Data Technology Co.ltdShanghaiChina
| | - Jing Wang
- Shanghai Long For Health Data Technology Co.ltdShanghaiChina
| | - Lvwen Liu
- Shanghai Long For Health Data Technology Co.ltdShanghaiChina
| | - Wei Zhang
- Department of BiostatisticsFudan University School of Public HealthShanghaiChina
| | - Yang Wang
- Department of UrologyThe Fifth People's Hospital of Shanghai, Fudan UniversityShanghaiChina
| | - Jindong Shi
- Department of Respiratory MedicineThe Fifth People's Hospital of Shanghai, Fudan UniversityShanghaiChina
| | - Ju Xia
- National Institute of Clinical Research, The Fifth People's Hospital of ShanghaiFudan UniversityShanghaiChina
| | - Yuting Gu
- National Institute of Clinical Research, The Fifth People's Hospital of ShanghaiFudan UniversityShanghaiChina
| | - Qingqing Qian
- National Institute of Clinical Research, The Fifth People's Hospital of ShanghaiFudan UniversityShanghaiChina
- Department of Pharmacy, The Fifth People's Hospital of ShanghaiFudan UniversityShanghaiChina
| | - Yang Hong
- National Institute of Clinical Research, The Fifth People's Hospital of ShanghaiFudan UniversityShanghaiChina
- Department of Osteology, The Fifth People's Hospital of ShanghaiFudan UniversityShanghaiChina
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Gu Y, Lin X, Dong Y, Wood G, Seidah NG, Werstuck G, Major P, Bonert M, Kapoor A, Tang D. PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2023; 42:2. [PMID: 36588164 PMCID: PMC9806914 DOI: 10.1186/s13046-022-02584-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9's oncogenic roles in melanoma and other cancers remain unclear. METHODS PCSK9's association with melanoma was analysed using the TCGA dataset. Empty vector (EV), PCSK9, gain-of-function (D374Y), and loss-of-function (Q152H) PCSK9 mutant were stably-expressed in murine melanoma B16 cells and studied for impact on B16 cell-derived oncogenesis in vitro and in vivo using syngeneic C57BL/6 and Pcsk9-/- mice. Intratumoral accumulation of cholesterol was determined. RNA-seq was performed on individual tumor types. Differentially-expressed genes (DEGs) were derived from the comparisons of B16 PCSK9, B16 D374Y, or B16 Q152H tumors to B16 EV allografts and analysed for pathway alterations. RESULTS PCSK9 expression and its network negatively correlated with the survival probability of patients with melanoma. PCSK9 promoted B16 cell proliferation, migration, and growth in soft agar in vitro, formation of tumors in C57BL/6 mice in vivo, and accumulation of intratumoral cholesterol in a manner reflecting its regulation of the low-density lipoprotein receptor (LDLR): Q152H, EV, PCSK9, and D374Y. Tumor-associated T cells, CD8 + T cells, and NK cells were significantly increased in D374Y tumors along with upregulations of multiple immune checkpoints, IFNγ, and 143 genes associated with T cell dysfunction. Overlap of 36 genes between the D374Y DEGs and the PCSK9 DEGs predicted poor prognosis of melanoma and resistance to immune checkpoint blockade (ICB) therapy. CYTH4, DENND1C, AOAH, TBC1D10C, EPSTI1, GIMAP7, and FASL (FAS ligand) were novel predictors of ICB therapy and displayed high level of correlations with multiple immune checkpoints in melanoma and across 30 human cancers. We observed FAS ligand being among the most robust biomarkers of ICB treatment and constructed two novel and effective multigene panels predicting response to ICB therapy. The profiles of allografts produced by B16 EV, PCSK9, D374Y, and Q152H remained comparable in C57BL/6 and Pcsk9-/- mice. CONCLUSIONS Tumor-derived PCSK9 plays a critical role in melanoma pathogenesis. PCSK9's oncogenic actions are associated with intratumoral cholesterol accumulation. PCSK9 systemically affects the immune system, contributing to melanoma immune evasion. Novel biomarkers derived from the PCSK9-network effectively predicted ICB therapy responses.
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Affiliation(s)
- Yan Gu
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Xiaozeng Lin
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Ying Dong
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Geoffrey Wood
- grid.34429.380000 0004 1936 8198Department of Pathology, University of Guelph, Guelph, ON N1G 2W1 Canada
| | - Nabil G. Seidah
- grid.511547.30000 0001 2106 1695Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute, University of Montreal, Montreal, QC H2W 1R7 Canada
| | - Geoff Werstuck
- grid.25073.330000 0004 1936 8227Department of Medicine, McMaster University, Hamilton, ON L8S 4K1 Canada
| | - Pierre Major
- grid.25073.330000 0004 1936 8227Department of Oncology, McMaster University, Hamilton, ON L8S 4K1 Canada
| | - Michael Bonert
- grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4K1 Canada
| | - Anil Kapoor
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
| | - Damu Tang
- grid.416721.70000 0001 0742 7355Urological Cancer Center for Research and Innovation (UCCRI), T3310, St. Joseph’s Hospital, 50 Charlton Ave East, Hamilton, ON L8N 4A6 Canada ,grid.25073.330000 0004 1936 8227Department of Surgery, McMaster University, Hamilton, ON L8S 4K1 Canada ,grid.416721.70000 0001 0742 7355The Research Institute of St Joe’s Hamilton, G344, St. Joseph’s Hospital, Hamilton, ON L8N 4A6 Canada
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13
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Dey A, Austin M, Kluger HM, Trunova N, Mann H, Shire N, Morgan C, Zhou D, Mugundu GM. Association between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab. Front Immunol 2022; 13:1026964. [PMID: 36405729 PMCID: PMC9670978 DOI: 10.3389/fimmu.2022.1026964] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/17/2022] [Indexed: 09/05/2024] Open
Abstract
PURPOSE Immune-mediated adverse events (imAEs) may be associated with response to immune checkpoint inhibitors. We assessed the relationship between imAE development and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab (anti-programmed cell death ligand-1 [PD-L1]) alone or in combination with tremelimumab (anti-cytotoxic T-lymphocyte-associated protein 4). METHODS The analysis used individual patient-level data from 307 and 310 patients in the monotherapy and combination arms of MYSTIC, respectively. We evaluated the association between treatment efficacy and development of imAEs using univariate and multivariate survival analyses. Using machine learning, we built a predictive model utilizing baseline clinical and laboratory features to identify patients at risk of developing imAEs and further evaluated patient survival based on a threshold index extracted from the model. RESULTS Patients who developed any grade of imAE had improved overall survival versus patients without (hazard ratio [HR] 0.51; 95% confidence interval [CI]: 0.41-0.62). imAE development was associated with improved overall survival (HR 0.54; 95% CI 0.44-0.66) in a multivariate Cox proportional hazard model considering patient demographic features and baseline characteristics. Higher odds of imAE development were observed (odds ratio 3.023; 95% CI: 1.56-5.83) in responders versus non-responders in patients treated with immunotherapy. Based on baseline characteristics, the random forest classification algorithm was used to formulate a predictive model to identify patients at increased risk of developing imAEs during treatment. CONCLUSION Post-hoc exploratory analysis found that the efficacy of immunotherapy was improved in patients who developed on-treatment imAEs. This was independent of severity of imAEs or the need for steroid treatment, which is important in allowing patients to remain on treatment and derive optimal clinical benefit. Further research is warranted to establish the correlation between incidence of imAEs and efficacy in this patient population.
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Affiliation(s)
- Agnish Dey
- Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, Boston, MA, United States
| | - Matthew Austin
- School of Medicine, Yale University, New Haven, CT, United States
| | | | - Nataliya Trunova
- Immuno-Oncology Franchise, Oncology R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Helen Mann
- Oncology Biometrics, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - Norah Shire
- Late Development Oncology, Oncology R&D, AstraZeneca, Gaithersburg, MD, United States
| | - Claire Morgan
- Patient Safety Oncology, AstraZeneca, Gaithersburg, MD, United States
| | - Diansong Zhou
- Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, Boston, MA, United States
| | - Ganesh M. Mugundu
- Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, Boston, MA, United States
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14
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Turner CN, Mullins GN, Hoyer KK. CXCR5 +CD8 T cells: Potential immunotherapy targets or drivers of immune-mediated adverse events? Front Med (Lausanne) 2022; 9:1034764. [PMID: 36314014 PMCID: PMC9606409 DOI: 10.3389/fmed.2022.1034764] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 09/23/2022] [Indexed: 11/15/2022] Open
Abstract
CXCR5+CD8 T cells have attracted significant interest within multiple areas of immunology, cancer, and infection. This is in part due to their apparent dual functionality. These cells perform as cytotoxic cells in a variety of infection states including LCMV, HBV, HIV and SIV. However, CXCR5+CD8 T cells also associate with B cells in peripheral organs and function to stimulate B cell proliferation, antibody/B cell receptor class-switch, and antibody production. CXCR5+CD8 T cells are similar to CXCR5+CD4 T follicular helpers in their genetic make-up, B cell interactions, and functionality despite possessing elevated programmed cell death 1 and cytotoxic proteins. Within cancer CXCR5+CD8 T cells have risen as potential prognostic markers for overall survival and are functionally cytotoxic within tumor microenvironments. In inflammatory disease and autoimmunity, CXCR5+CD8 T cells are implicated in disease progression. During viral infection and cancer, CXCR5 expression on CD8 T cells generally is indicative of progenitor memory stem-like exhausted cells, which are more responsive to immune checkpoint blockade therapy. The use of immune checkpoint inhibitors to overcome immune exhaustion in cancer, and subsequent consequence of immune adverse events, highlights the dual nature of the cellular immune response. This review will detail the functionality of CXCR5+CD8 T cells in cancer and autoimmunity with potential repercussions during immune checkpoint blockade therapy discussed.
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Affiliation(s)
- Christi N. Turner
- Quantitative and Systems Biology Graduate Program, University of California, Merced, Merced, CA, United States
| | - Genevieve N. Mullins
- Quantitative and Systems Biology Graduate Program, University of California, Merced, Merced, CA, United States
| | - Katrina K. Hoyer
- Quantitative and Systems Biology Graduate Program, University of California, Merced, Merced, CA, United States,Department of Molecular and Cell Biology, School of Natural Sciences, University of California, Merced, Merced, CA, United States,Health Sciences Research Institute, University of California, Merced, Merced, CA, United States,*Correspondence: Katrina K. Hoyer
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15
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Cardeña-Gutiérrez A, López Barahona M. Predictive Biomarkers of Severe Immune-Related Adverse Events With Immune Checkpoint Inhibitors: Prevention, Underlying Causes, Intensity, and Consequences. Front Med (Lausanne) 2022; 9:908752. [PMID: 35774996 PMCID: PMC9237384 DOI: 10.3389/fmed.2022.908752] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/11/2022] [Indexed: 11/13/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have dramatically transformed oncology by prolonging overall survival and yielding better patient tolerance compared to other chemotherapeutic agents. However, numerous questions remain unanswered about the toxicity profile of ICIs, its relationship with the treatment response, and causes underlying the excellent treatment response in some patients, while recalcitrance in others. Research groups have continued to seek biomarkers that may permit the identification of treatment responders and predict toxicity to facilitate cessation of immunotherapy before the development of severe toxicity. However, some studies have found associations between serious adverse events and longer survivorship. The research question entailed determining whether a biomarker is needed to predict severe immune-related adverse events prior to their development or whether providing early treatment for toxicity would inhibit the immune system from attaining a long-lasting anti-tumor effect. Therefore, this review conducted an in-depth analysis into the molecular basis of these observations.
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Affiliation(s)
- Ana Cardeña-Gutiérrez
- MedicalOncologyDepartment, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
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16
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Zhang K, Kong X, Li Y, Wang Z, Zhang L, Xuan L. PD-1/PD-L1 Inhibitors in Patients With Preexisting Autoimmune Diseases. Front Pharmacol 2022; 13:854967. [PMID: 35370736 PMCID: PMC8971753 DOI: 10.3389/fphar.2022.854967] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/17/2022] [Indexed: 02/04/2023] Open
Abstract
Autoimmune diseases and malignant tumors are the two hotspots and difficulties that are currently being studied and concerned by the medical field. The use of PD-1/PD-L1 inhibitors improves the prognosis of advanced tumors, but excessive immune responses can also induce immune-related adverse events (irAEs). Due to this concern, many clinical trials exclude cancer patients with preexisting autoimmune disease (AID). This review outlines the possible mechanisms of irAE, discusses the safety and efficacy of PD-1/PD-L1 inhibitors in cancer patients with preexisting AID, and emphasizes the importance of early recognition, continuous monitoring, and multidisciplinary cooperation in the prevention and management of cancer patients with preexisting AID.
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Affiliation(s)
- Ke Zhang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Li
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhongzhao Wang
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Zhongzhao Wang, ; Lin Zhang, ; Lixue Xuan,
| | - Lin Zhang
- School of Population Medicine and Public Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Melbourne School of Population and Global Health, the University of Melbourne, Melbourne, VIC, Australia
- Centre of Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia
- *Correspondence: Zhongzhao Wang, ; Lin Zhang, ; Lixue Xuan,
| | - Lixue Xuan
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Zhongzhao Wang, ; Lin Zhang, ; Lixue Xuan,
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Zhang W, Meng Y, Yang L, Shen M, Zhou L, Li R, Wang Y, Du W, Xiong Y, Han Y, Zhang X, Liu L, Ren X. Ferritin as a diagnostic, differential diagnostic, and prognostic marker for immune-related adverse events. Cancer Biol Med 2021; 18:j.issn.2095-3941.2021.0037. [PMID: 34378879 PMCID: PMC8610162 DOI: 10.20892/j.issn.2095-3941.2021.0037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 03/30/2021] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE Distinguishing immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) from the AEs caused by chemotherapy, targeted therapy, or infection is highly difficult. This study offers new insights into evaluating the diagnosis, differential diagnostic, and prognostic value of ferritin for irAEs induced by ICIs. METHODS From December 1, 2018, to April 1, 2019, we examined 318 patients with malignant tumors who received serum ferritin monitoring. The cohort comprised 231 patients treated with PD-1 inhibitor or combination with chemotherapy, and 87 patients treated with chemotherapy. Of the 231 patients, 90 had irAEs (irAE group), 70 had non-irAEs (non-irAE group), 67 had no AEs (no irAE-non irAE group), and 4 had unclassified AEs. In the 87 patients, 60 had AEs (AE group), and 27 had no AEs (no AE group). Statistical analyses were conducted with nonparametric Mann-Whitney tests. RESULTS At the onset of AEs in the irAE group, ferritin (normal range, 35-150 μg/L) rose to a median of 927 μg/L (range, 117-17,825 μg/L) from 86 μg/L at baseline (range, 29-421 μg/L) (P < 0.001). Ferritin levels at the onset of AEs in the irAE group were significantly higher than those in the non-irAE group (median, 81 μg/L; range, 32-478 μg/L) (P < 0.001) and the AE group (median, 103 μg/L; range, 23-712 μg/L) (P < 0.001). After treatment in the irAE group, ferritin continuously decreased to a normal range in recovered patients, showed no significant changes in stable patients, and continued to rise in patients who died. CONCLUSIONS Ferritin can be used as a diagnostic, differential diagnostic, and prognostic marker for irAEs in patients treated with ICIs.
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Affiliation(s)
- Weihong Zhang
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yuan Meng
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Lin Yang
- State Key Laboratory of Experimental Hematology, Peking Union Medical College, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin 300020, China
| | - Meng Shen
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Li Zhou
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Runmei Li
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yang Wang
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Weijiao Du
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yanjuan Xiong
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Ying Han
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Xinwei Zhang
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Liang Liu
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
| | - Xiubao Ren
- Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
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18
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Vito A, Salem O, El-Sayes N, MacFawn IP, Portillo AL, Milne K, Harrington D, Ashkar AA, Wan Y, Workenhe ST, Nelson BH, Bruno TC, Mossman KL. Immune checkpoint blockade in triple negative breast cancer influenced by B cells through myeloid-derived suppressor cells. Commun Biol 2021; 4:859. [PMID: 34253827 PMCID: PMC8275624 DOI: 10.1038/s42003-021-02375-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022] Open
Abstract
Triple negative breast cancer holds a dismal clinical outcome and as such, patients routinely undergo aggressive, highly toxic treatment regimens. Clinical trials for TNBC employing immune checkpoint blockade in combination with chemotherapy show modest prognostic benefit, but the percentage of patients that respond to treatment is low, and patients often succumb to relapsed disease. Here, we show that a combination immunotherapy platform utilizing low dose chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) increases tumor-infiltrating lymphocytes, in otherwise immune-bare tumors, allowing 60% of mice to achieve durable tumor regression when treated with immune checkpoint blockade. Whole-tumor RNA sequencing of mice treated with FEC + oHSV-1 shows an upregulation of B cell receptor signaling pathways and depletion of B cells prior to the start of treatment in mice results in complete loss of therapeutic efficacy and expansion of myeloid-derived suppressor cells. Additionally, RNA sequencing data shows that FEC + oHSV-1 suppresses genes associated with myeloid-derived suppressor cells, a key population of cells that drive immune escape and mediate therapeutic resistance. These findings highlight the importance of tumor-infiltrating B cells as drivers of antitumor immunity and their potential role in the regulation of myeloid-derived suppressor cells.
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Affiliation(s)
- Alyssa Vito
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Omar Salem
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Nader El-Sayes
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Ian P MacFawn
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Ana L Portillo
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Katy Milne
- Deeley Research Centre, BC Cancer, Victoria, BC, Canada
| | | | - Ali A Ashkar
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Yonghong Wan
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Samuel T Workenhe
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Brad H Nelson
- Deeley Research Centre, BC Cancer, Victoria, BC, Canada
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Tullia C Bruno
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Karen L Mossman
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.
- Department of Medicine, McMaster University, Hamilton, ON, Canada.
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19
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Yoon SJ, Lee CB, Chae SU, Jo SJ, Bae SK. The Comprehensive "Omics" Approach from Metabolomics to Advanced Omics for Development of Immune Checkpoint Inhibitors: Potential Strategies for Next Generation of Cancer Immunotherapy. Int J Mol Sci 2021; 22:6932. [PMID: 34203237 PMCID: PMC8268114 DOI: 10.3390/ijms22136932] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 12/11/2022] Open
Abstract
In the past decade, immunotherapies have been emerging as an effective way to treat cancer. Among several categories of immunotherapies, immune checkpoint inhibitors (ICIs) are the most well-known and widely used options for cancer treatment. Although several studies continue, this treatment option has yet to be developed into a precise application in the clinical setting. Recently, omics as a high-throughput technique for understanding the genome, transcriptome, proteome, and metabolome has revolutionized medical research and led to integrative interpretation to advance our understanding of biological systems. Advanced omics techniques, such as multi-omics, single-cell omics, and typical omics approaches, have been adopted to investigate various cancer immunotherapies. In this review, we highlight metabolomic studies regarding the development of ICIs involved in the discovery of targets or mechanisms of action and assessment of clinical outcomes, including drug response and resistance and propose biomarkers. Furthermore, we also discuss the genomics, proteomics, and advanced omics studies providing insights and comprehensive or novel approaches for ICI development. The overview of ICI studies suggests potential strategies for the development of other cancer immunotherapies using omics techniques in future studies.
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Affiliation(s)
| | | | | | | | - Soo Kyung Bae
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, Korea; (S.J.Y.); (C.B.L.); (S.U.C.); (S.J.J.)
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20
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Abstract
Immunotherapy has changed the landscape of cancer treatment and has significantly improved the outcome of several cancer types including breast, lung, colorectal and prostate. Neoantigen recognition and immune checkpoint inhibitors are nowadays the milestones of different immunotherapeutic regimes; however, high cost, primary and acquired resistance and the high variability of responses make their extensive use difficult. The development of better predictive biomarkers that represent tumour diversity shows promise because there is a significant body of clinical data showing a spectrum of immunotherapeutic responses that might be related back to their specific characteristics. This article makes a conceptual and historical review to summarise the main advances in our understanding of the role of the immune system in cancer, while describing the methodological details that have been successfully implemented on cancer treatments and that may hold the key to improved therapeutic approaches.
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21
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Budczies J, Kirchner M, Kluck K, Kazdal D, Glade J, Allgäuer M, Kriegsmann M, Heußel CP, Herth FJ, Winter H, Meister M, Muley T, Fröhling S, Peters S, Seliger B, Schirmacher P, Thomas M, Christopoulos P, Stenzinger A. A gene expression signature associated with B cells predicts benefit from immune checkpoint blockade in lung adenocarcinoma. Oncoimmunology 2021; 10:1860586. [PMID: 33520406 PMCID: PMC7808386 DOI: 10.1080/2162402x.2020.1860586] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 11/09/2020] [Accepted: 12/01/2020] [Indexed: 01/19/2023] Open
Abstract
Immune checkpoint blockade (ICB) expands the therapeutic options for metastatic lung cancer nowadays representing a standard frontline strategy as monotherapy or combination therapy, as well as an option in oncogene-addicted NSCLC after exhaustion of targeted therapies. Predictive markers are urgently needed, since only a minority of patients benefits from ICB, while serious adverse effects of immunotoxicity may occur. The study cohort included 43 ICB-treated metastatic lung adenocarcinoma showing long-term response (n = 16), rapid progression (n = 21) or intermediate patterns of response (n = 6). Lung biopsies acquired before initiation of ICB were analyzed by targeted mRNA expression profiling of 770 genes. Level and proportions of 14 immune cell types were estimated using characteristic gene expression signatures. Abundance of B cells (HR = 0.66, p = .00074), CD45+ cells (HR = 0.61, p = .01) and total TILs (HR = 0.62, p = .025) was associated with prolonged progression-free survival after ICB treatment. In a ROC analysis, B cells (AUC = 0.77, p = .0055) and CD45+ cells (AUC = 0.73, p = .019) predicted benefit of ICB, which was not the case for PD-L1 mRNA (AUC = 0.54, p = .72) and PD-L1 protein expression (AUC = 0.68, p = .082). Clustering of 79 candidate predictive markers identified among 770 investigated genes revealed two distinct predictive clusters which included cytotoxic cell or macrophage markers, respectively. In summary, targeted gene expression profiling was feasible using routine diagnostics biopsies. This study proposes B cells and total TILs as complementary predictors of ICB benefit in NSCLC. While further preferably prospective validation is required, gene expression profiling could be integrated in the routine diagnostic work-up complementing existing NGS protocols.
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Affiliation(s)
- Jan Budczies
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martina Kirchner
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Klaus Kluck
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel Kazdal
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Julia Glade
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Michael Allgäuer
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Mark Kriegsmann
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
| | - Claus-Peter Heußel
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
- Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany
| | - Felix J. Herth
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Pneumology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
| | - Hauke Winter
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Thoracic Surgery, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
| | - Michael Meister
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Muley
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan Fröhling
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Translational Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Solange Peters
- Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, Lausanne, Switzerland
| | - Barbara Seliger
- Institute for Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Peter Schirmacher
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Thomas
- Department of Thoracic Surgery, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases at Heidelberg University Hospital, Heidelberg, Germany
| | - Petros Christopoulos
- Department of Thoracic Surgery, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases at Heidelberg University Hospital, Heidelberg, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
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22
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Schoenberg E, Colombe B, Cha J, Orloff M, Shalabi D, Ross NA, Dasgeb B. Pemphigus associated with ipilimumab therapy. Int J Dermatol 2021; 60:e331-e333. [PMID: 33410503 DOI: 10.1111/ijd.15405] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 11/05/2020] [Accepted: 12/10/2020] [Indexed: 12/27/2022]
Affiliation(s)
- Elizabeth Schoenberg
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Beth Colombe
- Histocompatibility and Tissue Typing Laboratory, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jisun Cha
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Marlana Orloff
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Doaa Shalabi
- SUNY Downstate Health Sciences University College of Medicine, Brooklyn, NY, USA
| | - Nicholas A Ross
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Bahar Dasgeb
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.,Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA
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23
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Lee B, Lee H, Huh J, Yoon CJ, Oh SJ, Song K, Jeong S, Kim J, Lee K, Shin BS, Jeong JH, Kim TW, Lee J. Human Ferritin Platform and Its Optimized Structures to Enhance Anti‐Cancer Immunity. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.202000208] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Bo‐Ram Lee
- Department of Chemical and Biological Engineering Korea University Seoul 136–713 Republic of Korea
| | - Hyo‐Jung Lee
- Laboratory of Tumor Immunology Department of Biomedical Sciences Graduate School of Medicine Korea University Seoul 136–713 Republic of Korea
- Department of Biochemistry and Molecular Biology College of Medicine Korea University Seoul 136–713 Republic of Korea
- Department of Biomedical Science College of Medicine Korea University Seoul 136–713 Republic of Korea
| | - June Huh
- Department of Chemical and Biological Engineering Korea University Seoul 136–713 Republic of Korea
| | - Chul Joo Yoon
- Department of Chemical and Biological Engineering Korea University Seoul 136–713 Republic of Korea
| | - Se Jin Oh
- Laboratory of Tumor Immunology Department of Biomedical Sciences Graduate School of Medicine Korea University Seoul 136–713 Republic of Korea
- Department of Biochemistry and Molecular Biology College of Medicine Korea University Seoul 136–713 Republic of Korea
- Department of Biomedical Science College of Medicine Korea University Seoul 136–713 Republic of Korea
| | - Kwon‐Ho Song
- Laboratory of Tumor Immunology Department of Biomedical Sciences Graduate School of Medicine Korea University Seoul 136–713 Republic of Korea
- Department of Biochemistry and Molecular Biology College of Medicine Korea University Seoul 136–713 Republic of Korea
- Department of Biomedical Science College of Medicine Korea University Seoul 136–713 Republic of Korea
| | - Sojin Jeong
- Department of Chemical and Biological Engineering Korea University Seoul 136–713 Republic of Korea
| | - Jungwon Kim
- Department of Biochemistry and Molecular Biology College of Medicine Korea University Seoul 136–713 Republic of Korea
- Department of Biomedical Science College of Medicine Korea University Seoul 136–713 Republic of Korea
| | - Kyung‐Mi Lee
- Department of Biochemistry and Molecular Biology College of Medicine Korea University Seoul 136–713 Republic of Korea
- Department of Biomedical Science College of Medicine Korea University Seoul 136–713 Republic of Korea
| | - Beom Soo Shin
- School of Pharmacy Sungkyunkwan University Suwon 16419 Republic of Korea
| | - Ji Hoon Jeong
- School of Pharmacy Sungkyunkwan University Suwon 16419 Republic of Korea
| | - Tae Woo Kim
- Laboratory of Tumor Immunology Department of Biomedical Sciences Graduate School of Medicine Korea University Seoul 136–713 Republic of Korea
- Department of Biochemistry and Molecular Biology College of Medicine Korea University Seoul 136–713 Republic of Korea
- Department of Biomedical Science College of Medicine Korea University Seoul 136–713 Republic of Korea
- Translational Research Institute for Incurable Diseases College of Medicine Korea University Seoul 136–713 Republic of Korea
| | - Jeewon Lee
- Department of Chemical and Biological Engineering Korea University Seoul 136–713 Republic of Korea
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24
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Bruni D, Angell HK, Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer 2020; 20:662-680. [PMID: 32753728 DOI: 10.1038/s41568-020-0285-7] [Citation(s) in RCA: 1023] [Impact Index Per Article: 204.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/22/2020] [Indexed: 12/15/2022]
Abstract
The international American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumour-node-metastasis (TNM) staging system provides the current guidelines for the classification of cancer. However, among patients within the same stage, the clinical outcome can be very different. More recently, a novel definition of cancer has emerged, implicating at all stages a complex and dynamic interaction between tumour cells and the immune system. This has enabled the definition of the immune contexture, representing the pre-existing immune parameters associated with patient survival. Even so, the role of distinct immune cell types in modulating cancer progression is increasingly emerging. An immune-based assay named the 'Immunoscore' was defined to quantify the in situ T cell infiltrate and was demonstrated to be superior to the AJCC/UICC TNM classification for patients with colorectal cancer. This Review provides a broad overview of the main immune parameters positively or negatively shaping cancer development, including the Immunoscore, and their prognostic and predictive value. The importance of the immune system in cancer control is demonstrated by the requirement for a pre-existing intratumour adaptive immune response for effective immunotherapies, such as checkpoint inhibitors. Finally, we discuss how the combination of multiple immune parameters, rather than individual ones, might increase prognostic and/or predictive power.
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Affiliation(s)
- Daniela Bruni
- INSERM, Laboratory of Integrative Cancer Immunology; Équipe Labellisée Ligue Contre le Cancer; Sorbonne Université; Sorbonne Paris Cité; Université de Paris; Centre de Recherche des Cordeliers, Paris, France
| | - Helen K Angell
- Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Jérôme Galon
- INSERM, Laboratory of Integrative Cancer Immunology; Équipe Labellisée Ligue Contre le Cancer; Sorbonne Université; Sorbonne Paris Cité; Université de Paris; Centre de Recherche des Cordeliers, Paris, France.
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25
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Vitamin D, autoimmunity and immune-related adverse events of immune checkpoint inhibitors. Arch Dermatol Res 2020; 313:1-10. [PMID: 32519001 DOI: 10.1007/s00403-020-02094-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/26/2020] [Accepted: 05/29/2020] [Indexed: 12/16/2022]
Abstract
In addition to its quintessential role in bone homeostasis, vitamin D also plays an important role in regulating the immune system. As such, many studies have demonstrated the therapeutic benefit of vitamin D in treating autoimmune diseases. This immunomodulatory activity of vitamin D has recently attracted more attention due to the rapid development of immunotherapies for cancers, including melanoma. Patients on cancer immunotherapies can suffer from immune-related adverse events (irAEs), which can involve any organ system and range from common dermatological reactions to extremely severe cases of fatal myocarditis in metastatic melanoma patients. Since there are currently no effective approaches to predict or prevent irAEs, it is attractive to potentially leverage the intriguing immunomodulatory effects of vitamin D within this context. This review will discuss recent research investigating the possibility of using vitamin D to alleviate autoimmunity and irAEs with the hope of improving outcomes for patients on cancer immunotherapies, especially within the context of dermatology.
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Martins F, Sykiotis GP, Maillard M, Fraga M, Ribi C, Kuntzer T, Michielin O, Peters S, Coukos G, Spertini F, Thompson JA, Obeid M. New therapeutic perspectives to manage refractory immune checkpoint-related toxicities. Lancet Oncol 2020; 20:e54-e64. [PMID: 30614479 DOI: 10.1016/s1470-2045(18)30828-3] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/09/2018] [Accepted: 10/30/2018] [Indexed: 12/14/2022]
Abstract
Immune checkpoint inhibitors are reshaping the prognosis of many cancer and are progressively becoming the standard of care in the treatment of many tumour types. Immunotherapy is bringing new hope to patients, but also a whole new spectrum of toxicities for healthcare practitioners to manage. Oncologists and specialists involved in the pluridisciplinary management of patients with cancer are increasingly confronted with the therapeutic challenge of treating patients with severe and refractory immune-related adverse events. In this Personal View, we summarise the therapeutic strategies that have been used to manage such toxicities resulting from immune checkpoint inhibitor treatment. On the basis of current knowledge about their pathogenesis, we discuss the use of new biological and non-biological immunosuppressive drugs to treat severe and steroid refractory immune-related adverse events. Depending on the immune infiltrate type that is predominant, we propose a treatment algorithm for personalised management that goes beyond typical corticosteroid use. We propose a so-called shut-off strategy that aims at inhibiting key inflammatory components involved in the pathophysiological processes of immune-related adverse events, and limits potential adverse effects of drug immunosuppression on tumour response. This approach develops on current guidelines and challenges the step-by-step increase approach to drug immunosuppression.
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Affiliation(s)
- Filipe Martins
- Département d'Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Gerasimos P Sykiotis
- Service d'Endocrinologie, Diabétologie, et Métabolisme, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Michel Maillard
- Service de Gastro-entérologie et Hépatologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Crohn's and Colitis Center, Lausanne, Switzerland
| | - Montserrat Fraga
- Service de Gastro-entérologie et Hépatologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Camillo Ribi
- Service Immunologie et Allergie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Thierry Kuntzer
- Service de Neurologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Olivier Michielin
- Département d'Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Solange Peters
- Département d'Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Georges Coukos
- Département d'Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Ludwig Institute for Cancer Research, Epalinges, Switzerland
| | - Francois Spertini
- Service Immunologie et Allergie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - John A Thompson
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA; National Cancer Institute, Bethesda, MA, USA
| | - Michel Obeid
- Service Immunologie et Allergie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Centre d'Immunothérapie et de Vaccinologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Faculté Médecine Paris Descartes, Université Paris Descartes, Paris, France.
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27
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Chen VE, Greenberger BA, Taylor JM, Edelman MJ, Lu B. The Underappreciated Role of the Humoral Immune System and B Cells in Tumorigenesis and Cancer Therapeutics: A Review. Int J Radiat Oncol Biol Phys 2020; 108:38-45. [PMID: 32251756 DOI: 10.1016/j.ijrobp.2020.03.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 03/21/2020] [Indexed: 02/07/2023]
Abstract
The advent of immunotherapy has ushered in a new era in both cancer research and cancer treatment strategies. Published reviews have described potential mechanisms for therapeutic synergisms from the combination of radiation therapy and immunotherapy, largely overlooking the role of humoral immunity by only focusing on cellular immunity. Given that these 2 branches of the immune system are highly interdependent, in this review we detail both what has already been established regarding the role of humoral immunity in cancer and propose potential avenues that are ripe for further investigation and potential clinical applications.
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Affiliation(s)
- Victor E Chen
- Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Benjamin A Greenberger
- Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - James M Taylor
- Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Martin J Edelman
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Bo Lu
- Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, Pennsylvania.
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28
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Esfahani K, Roudaia L, Buhlaiga N, Del Rincon SV, Papneja N, Miller WH. A review of cancer immunotherapy: from the past, to the present, to the future. ACTA ACUST UNITED AC 2020; 27:S87-S97. [PMID: 32368178 DOI: 10.3747/co.27.5223] [Citation(s) in RCA: 602] [Impact Index Per Article: 120.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Compared with previous standards of care (including chemotherapy, radiotherapy, and surgery), cancer immunotherapy has brought significant improvements for patients in terms of survival and quality of life. Immunotherapy has now firmly established itself as a novel pillar of cancer care, from the metastatic stage to the adjuvant and neoadjuvant settings in numerous cancer types. In this review article, we highlight how the history of cancer immunotherapy paved the way for discoveries that are now part of the standard of care. We also highlight the current pitfalls and limitations of cancer checkpoint immunotherapy and how novel research in the fields of personalized cancer vaccines, autoimmunity, the microbiome, the tumour microenvironment, and metabolomics is aiming to solve those challenges.
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Affiliation(s)
- K Esfahani
- Departments of Medicine and Oncology, Segal Cancer Centre, Sir Mortimer B. Davis Jewish General Hospital, Rossy Cancer Network, McGill University, Montreal, QC
| | - L Roudaia
- Departments of Medicine and Oncology, Segal Cancer Centre, Sir Mortimer B. Davis Jewish General Hospital, Rossy Cancer Network, McGill University, Montreal, QC
| | - N Buhlaiga
- Departments of Medicine and Oncology, Segal Cancer Centre, Sir Mortimer B. Davis Jewish General Hospital, Rossy Cancer Network, McGill University, Montreal, QC
| | - S V Del Rincon
- Department of Oncology, Lady Davis Institute, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, QC
| | - N Papneja
- Departments of Medicine and Oncology, Segal Cancer Centre, Sir Mortimer B. Davis Jewish General Hospital, Rossy Cancer Network, McGill University, Montreal, QC
| | - W H Miller
- Departments of Medicine and Oncology, Segal Cancer Centre, Sir Mortimer B. Davis Jewish General Hospital, Rossy Cancer Network, McGill University, Montreal, QC
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29
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Filipovic A, Miller G, Bolen J. Progress Toward Identifying Exact Proxies for Predicting Response to Immunotherapies. Front Cell Dev Biol 2020; 8:155. [PMID: 32258034 PMCID: PMC7092703 DOI: 10.3389/fcell.2020.00155] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 02/26/2020] [Indexed: 12/14/2022] Open
Abstract
Clinical value and utility of checkpoint inhibitors, a drug class targeting adaptive immune suppression pathways (PD-1, PDL-1, and CTLA-4), is growing rapidly and maintains status of a landmark achievement in oncology. Their efficacy has transformed life expectancy in multiple deadly cancer types (melanoma, lung cancer, renal/urothelial carcinoma, certain colorectal cancers, lymphomas, etc.). Despite significant clinical development efforts, therapeutic indication of approved checkpoint inhibitors are not as wide as the oncology community and patients would like them to be, potentially bringing into question their universal efficacy across tumor histologies. With the main goal of expanding immunotherapy applications, identifying of biomarkers to accurately predict therapeutic response and treatment related side-effects are a paramount need in the field. Specificities surrounding checkpoint inhibitors in clinic, such as unexpected tumor response patterns (pseudo- and hyper-progression), late responders, as well as specific immune mediated toxicities, complicate the management of patients. They stem from the complexities and dynamics of the tumor/host immune interactions, as well as baseline tumor biology. Search for clinically effective biomarkers therefore calls for a holistic approach, rather than implementation of a single analyte. The goal is to achieve dynamic and comprehensive acquisition, analyses and interpretation of immunological and biologic information about the tumor and the immune system, and to compute these parameters into an actionable, maximally predictive value at the individual patient level. Limitation delaying swift incorporation of validated immuno-oncology biomarkers span from standardized biospecimens acquisition and processing, selection of proficient biomarker discovery and validation methods, to establishing multidisciplinary consortiums and data sharing platforms. Multi-disciplinary efforts have already yielded some approved (PDL-1 and MSI-status) and other advanced tests (TMB, neoantigen pattern, and TIL infiltration rate). Importantly, clinical trial taskforces now recognize the imperative of the biomarker-driven trial design and execution, to enable translating biomarker discoveries into the clinical setting. This will ensure we utilize the “conspiracy” between the peripheral and intra-tumoral dynamic markers in shaping responses to checkpoint blockade, for the ultimate patient benefit.
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Affiliation(s)
| | - George Miller
- New York University School of Medicine, New York, NY, United States
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30
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Topp MS, Duell J, Guijarro AMA, Odin M, Nielsen T, Rajeswaran A, Wenger M, Zundel C, Bogucka-Fedorczuk A, Wrobel T. Severe treatment-refractory T-cell-mediated immune skin toxicities observed with obinutuzumab/rituximab-atezo-pola in two patients with follicular lymphoma. Haematologica 2020; 105:e256-e260. [PMID: 32029506 DOI: 10.3324/haematol.2019.233189] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- Max S Topp
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | - Johannes Duell
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | | | | | | | | | | | | | | | - Tomasz Wrobel
- Department of Hematology, Wrocław Medical University, Wrocław, Poland
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31
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Dhodapkar KM. Autoimmune complications of cancer immunotherapy. Curr Opin Immunol 2019; 61:54-59. [PMID: 31557690 DOI: 10.1016/j.coi.2019.08.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 07/25/2019] [Accepted: 08/26/2019] [Indexed: 12/31/2022]
Abstract
Immunotherapy of cancer with blockade of inhibitory immune checkpoints and adoptive cell therapies have led to impressive clinical responses in several cancers. However, with increasing utilization of these therapies, immune-related adverse events have emerged as a major obstacle. Herein I discuss recent insights into the immunobiology of these toxicities. Deeper understanding of the underlying pathogenic mechanisms, cellular and molecular pathways involved, similarities and differences with spontaneous autoimmunity, and identification of clinically relevant predictive biomarkers is needed to develop optimal approaches to prevent and treat these toxicities, without compromising the therapeutic benefit from these immune therapies. These events may also provide a unique window into mechanisms underlying spontaneous autoimmunity.
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Affiliation(s)
- Kavita M Dhodapkar
- Emory University and Children's Healthcare of Atlanta, Atlanta, GA, United States.
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32
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Zhuang Y, Zhang C, Wu Q, Zhang J, Ye Z, Qian Q. Application of immune repertoire sequencing in cancer immunotherapy. Int Immunopharmacol 2019; 74:105688. [PMID: 31276974 DOI: 10.1016/j.intimp.2019.105688] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 05/05/2019] [Accepted: 06/05/2019] [Indexed: 12/21/2022]
Abstract
With the prominent breakthrough in the field of tumor immunology, diverse cancer immunotherapies have attracted great attention in the last decade. The immune checkpoint inhibitors, adoptive cell therapies, and therapeutic cancer vaccines have already achieved impressive clinical success. However, the fact that only a small subset of patients with specific tumor types can benefit from these treatments limits the application of cancer immunotherapy. To seek out the molecular mechanisms behind this challenge and to select cancer precision medicine for different individuals, researchers apply the immune repertoire sequencing (IRS) to evaluate genetic responses of each patient to current immunotherapies. This review summarizes the technical advances and recent applications of IRS in cancer immunotherapy, indicates the limitations of this technique, and predicts future perspectives both in basic studies and clinical trials.
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Affiliation(s)
- Yuan Zhuang
- Shanghai Baize Medical Laboratory, Shanghai, China
| | - Changzheng Zhang
- Shanghai Baize Medical Laboratory, Shanghai, China; Shanghai Engineering Research Center for Cell Therapy, Shanghai, China
| | - Qiong Wu
- Shanghai Baize Medical Laboratory, Shanghai, China
| | - Jing Zhang
- Shanghai Baize Medical Laboratory, Shanghai, China
| | - Zhenlong Ye
- Shanghai Baize Medical Laboratory, Shanghai, China; Shanghai Cell Therapy Research Institute, Shanghai, China; Shanghai Engineering Research Center for Cell Therapy, Shanghai, China.
| | - Qijun Qian
- Shanghai Baize Medical Laboratory, Shanghai, China; Shanghai Cell Therapy Research Institute, Shanghai, China; Shanghai Engineering Research Center for Cell Therapy, Shanghai, China.
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33
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Rui X, Gu TT, Pan HF, Zhang HZ. Evaluation of PD-L1 biomarker for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatments for urothelial carcinoma patients: A meta-analysis. Int Immunopharmacol 2019; 67:378-385. [DOI: 10.1016/j.intimp.2018.12.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 11/21/2018] [Accepted: 12/07/2018] [Indexed: 01/22/2023]
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34
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Chatterjee G, Pai T, Hardiman T, Avery-Kiejda K, Scott RJ, Spencer J, Pinder SE, Grigoriadis A. Molecular patterns of cancer colonisation in lymph nodes of breast cancer patients. Breast Cancer Res 2018; 20:143. [PMID: 30458865 PMCID: PMC6247766 DOI: 10.1186/s13058-018-1070-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Lymph node (LN) metastasis is an important prognostic parameter in breast carcinoma, a crucial site for tumour–immune cell interaction and a gateway for further dissemination of tumour cells to other metastatic sites. To gain insight into the underlying molecular changes from the pre-metastatic, via initial colonisation to the fully involved LN, we reviewed transcriptional research along the evolving microenvironment of LNs in human breast cancers patients. Gene expression studies were compiled and subjected to pathway-based analyses, with an emphasis on immune cell-related genes. Of 366 studies, 14 performed genome-wide gene expression comparisons and were divided into six clinical-biological scenarios capturing different stages of the metastatic pathway in the LN, as follows: metastatically involved LNs are compared to their patient-matched primary breast carcinomas (scenario 1) or the normal breast tissue (scenario 2). In scenario 3, uninvolved LNs were compared between LN-positive patients and LN-negative patients. Scenario 4 homed in on the residual uninvolved portion of involved LNs and compared it to the patient-matched uninvolved LNs. Scenario 5 contrasted uninvolved and involved LNs, whilst in scenario 6 involved (sentinel) LNs were assessed between patients with other either positive or negative LNs (non-sentinel). Gene lists from these chronological steps of LN metastasis indicated that gene patterns reflecting deficiencies in dendritic cells and hyper-proliferation of B cells parallel to tumour promoting pathways, including cell adhesion, extracellular matrix remodelling, cell motility and DNA repair, play key roles in the changing microenvironment of a pro-metastatic to a metastatically involved LN. Similarities between uninvolved LNs and the residual uninvolved portion of involved LNs hinted that LN alterations expose systemic tumour-related immune responses in breast cancer patients. Despite the diverse settings, gene expression patterns at different stages of metastatic colonisation in LNs were recognised and may provide potential avenues for clinical interventions to counteract disease progression for breast cancer patients.
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Affiliation(s)
- Gaurav Chatterjee
- Cancer Bioinformatics, King's College London, Innovation Hub, Cancer Centre at Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.,School of Cancer & Pharmaceutical Sciences, CRUK King's Health Partners Centre, King's College London, Innovation Hub, Comprehensive Cancer Centre at Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.,Department of Pathology, Tata Memorial Centre, 8th Floor, Annexe Building, Mumbai, India
| | - Trupti Pai
- Cancer Bioinformatics, King's College London, Innovation Hub, Cancer Centre at Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.,School of Cancer & Pharmaceutical Sciences, CRUK King's Health Partners Centre, King's College London, Innovation Hub, Comprehensive Cancer Centre at Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.,Department of Pathology, Tata Memorial Centre, 8th Floor, Annexe Building, Mumbai, India
| | - Thomas Hardiman
- Cancer Bioinformatics, King's College London, Innovation Hub, Cancer Centre at Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.,School of Cancer & Pharmaceutical Sciences, CRUK King's Health Partners Centre, King's College London, Innovation Hub, Comprehensive Cancer Centre at Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - Kelly Avery-Kiejda
- Priority Research Centre for Cancer, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, NSW, 2308, Australia
| | - Rodney J Scott
- Priority Research Centre for Cancer, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, NSW, 2308, Australia
| | - Jo Spencer
- Peter Gorer Department of Immunobiology, King's College London, Guy's Hospital, 2nd Floor, Borough Wing, London, SE1 9RT, UK
| | - Sarah E Pinder
- School of Cancer & Pharmaceutical Sciences, CRUK King's Health Partners Centre, King's College London, Innovation Hub, Comprehensive Cancer Centre at Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - Anita Grigoriadis
- Cancer Bioinformatics, King's College London, Innovation Hub, Cancer Centre at Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK. .,School of Cancer & Pharmaceutical Sciences, CRUK King's Health Partners Centre, King's College London, Innovation Hub, Comprehensive Cancer Centre at Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK. .,Breast Cancer Now Research Unit, Innovation Hub, Cancer Centre at Guy's Hospital, King's College London, Faculty of Life Sciences and Medicine, London, SE1 9RT, UK.
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35
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B cells and antibody production in melanoma. Mamm Genome 2018; 29:790-805. [DOI: 10.1007/s00335-018-9778-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 08/24/2018] [Indexed: 01/12/2023]
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Jaafar J, Fernandez E, Alwan H, Philippe J. Programmed cell death-1 and programmed cell death ligand-1 antibodies-induced dysthyroidism. Endocr Connect 2018; 7:R196-R211. [PMID: 29739808 PMCID: PMC5937198 DOI: 10.1530/ec-18-0079] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 04/09/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND Monoclonal antibodies blocking the programmed cell death-1 (PD-1) or its ligand (PD-L1) are a group of immune checkpoints inhibitors (ICIs) with proven antitumor efficacy. However, their use is complicated by immune-related adverse events (irAEs), including endocrine adverse events (eAEs). PURPOSE We review the incidence, time to onset and resolution rate of dysthyroidism induced by PD-1/PD-L1 Ab, and the clinical, biological and radiological findings. We aim to discuss the potential mechanisms of PD-1/PD-L1 Ab-induced dysthyroidism, and to propose a management algorithm. METHODS We performed a literature search of available clinical trials regarding PD-1/PD-L1 Ab in the PubMed database. We selected all English language clinical trials that included at least 100 patients. We also present selected case series or reports, retrospective studies and reviews related to this issue. FINDINGS In patients treated with PD-1 Ab, hypothyroidism occurred in 2-10.1% and hyperthyroidism occurred in 0.9-7.8%. When thyroiditis was reported separately, it occurred in 0.34-2.6%. Higher rates were reported when PD-1 Ab were associated with other ICI or chemotherapy. The median time to onset of hyperthyroidism and hypothyroidism after PD-1 Ab initiation was 23-45 days and 2-3.5 months, respectively. Regarding PD-L1 Ab, hypothyroidism occurred in 0-10% and hyperthyroidism in 0.5-2% of treated patients. The average time to onset of dysthyroidism after PD-L1 Ab was variable and ranged from 1 day after treatment initiation to 31 months. CONCLUSION Dysthyroidism occurs in up to 10% of patients treated with PD-1/PD-L1 Ab. Hypothyroidism and reversible destructive thyroiditis are the most frequent endocrine adverse events (eAE) in PD-1/PD-L1 treated patients. Immune and non-immune mechanisms are potentially involved, independently of the presence of thyroid antibodies.
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Affiliation(s)
- Jaafar Jaafar
- Division of Endocrinology and DiabetologyGeneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Eugenio Fernandez
- Department of OncologyGeneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Heba Alwan
- Division of Endocrinology and DiabetologyGeneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - Jacques Philippe
- Division of Endocrinology and DiabetologyGeneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
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