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COVID-19 and immune checkpoint inhibitors: initial considerations.
Sullivan RJ, Johnson DB, Rini BI, Neilan TG, Lovly CM, Moslehi JJ, Reynolds KL
(2020) J Immunother Cancer 8:
MeSH Terms: Antineoplastic Agents, Immunological, Coronavirus Infections, Humans, Molecular Targeted Therapy, Neoplasms, Pandemics, Pneumonia, Viral, Programmed Cell Death 1 Receptor
Show Abstract · Added May 29, 2020
COVID-19 infections are characterized by inflammation of the lungs and other organs that ranges from mild and asymptomatic to fulminant and fatal. Patients who are immunocompromised and those with cardiopulmonary comorbidities appear to be particularly afflicted by this illness. During pandemic conditions, many aspects of cancer care have been impacted. One important clinical question is how to manage patients who need anticancer therapy, including immune checkpoint inhibitors (ICIs) during these conditions. Herein, we consider diagnostic and therapeutic implications of using ICI during this unprecedented period of COVID-19 infections. In particular, we consider the impact of ICI on COVID-19 severity, decisions surrounding continuing or interrupting therapy, diagnostic measures in patients with symptoms or manifestations potentially consistent with either COVID-19 or ICI toxicity, and resumption of therapy in infected patients. While more robust data are needed to guide clinicians on management of patients with cancer who may be affected by COVID-19, we hope this commentary provides useful insights for the clinical community.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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8 MeSH Terms
Increased reporting of fatal hepatitis associated with immune checkpoint inhibitors.
Vozy A, De Martin E, Johnson DB, Lebrun-Vignes B, Moslehi JJ, Salem JE
(2019) Eur J Cancer 123: 112-115
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, B7-H1 Antigen, CTLA-4 Antigen, Chemical and Drug Induced Liver Injury, Child, Databases, Factual, Female, Hepatitis, Autoimmune, Humans, Ipilimumab, Male, Massive Hepatic Necrosis, Middle Aged, Neoplasms, Nivolumab, Programmed Cell Death 1 Receptor, World Health Organization, Young Adult
Added November 12, 2019
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23 MeSH Terms
A case report of clonal EBV-like memory CD4 T cell activation in fatal checkpoint inhibitor-induced encephalitis.
Johnson DB, McDonnell WJ, Gonzalez-Ericsson PI, Al-Rohil RN, Mobley BC, Salem JE, Wang DY, Sanchez V, Wang Y, Chastain CA, Barker K, Liang Y, Warren S, Beechem JM, Menzies AM, Tio M, Long GV, Cohen JV, Guidon AC, O'Hare M, Chandra S, Chowdhary A, Lebrun-Vignes B, Goldinger SM, Rushing EJ, Buchbinder EI, Mallal SA, Shi C, Xu Y, Moslehi JJ, Sanders ME, Sosman JA, Balko JM
(2019) Nat Med 25: 1243-1250
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, CD4-Positive T-Lymphocytes, Encephalitis, Female, Herpesvirus 4, Human, Humans, Immunologic Memory, Lymphocyte Activation, Male, Middle Aged, Programmed Cell Death 1 Receptor, Young Adult
Show Abstract · Added November 12, 2019
Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45ROGZMBKi67) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 and CD8 T cells as culprits of checkpoint inhibitor-associated immune encephalitis.
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MeSH Terms
Abatacept for Severe Immune Checkpoint Inhibitor-Associated Myocarditis.
Salem JE, Allenbach Y, Vozy A, Brechot N, Johnson DB, Moslehi JJ, Kerneis M
(2019) N Engl J Med 380: 2377-2379
MeSH Terms: Abatacept, Aged, Antineoplastic Agents, Immunological, Female, Humans, Immunosuppressive Agents, Lung Neoplasms, Myocarditis, Myositis, Nivolumab, Programmed Cell Death 1 Receptor
Added November 12, 2019
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MeSH Terms
Immune checkpoint inhibitor-associated hypophysitis-World Health Organisation VigiBase report analysis.
Guerrero E, Johnson DB, Bachelot A, Lebrun-Vignes B, Moslehi JJ, Salem JE
(2019) Eur J Cancer 113: 10-13
MeSH Terms: Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, B7-H1 Antigen, CTLA-4 Antigen, Databases, Factual, Female, Humans, Hypophysitis, Ipilimumab, Male, Middle Aged, Nivolumab, Pharmacovigilance, Programmed Cell Death 1 Receptor, World Health Organization, Young Adult
Added November 12, 2019
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20 MeSH Terms
Hematologic Complications of Immune Checkpoint Inhibitors.
Davis EJ, Salem JE, Young A, Green JR, Ferrell PB, Ancell KK, Lebrun-Vignes B, Moslehi JJ, Johnson DB
(2019) Oncologist 24: 584-588
MeSH Terms: Adult, Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, B7-H1 Antigen, Databases, Factual, Female, Hematologic Diseases, Humans, Incidence, Ipilimumab, Male, Middle Aged, Neoplasms, Pharmacovigilance, Programmed Cell Death 1 Receptor, Risk Factors
Show Abstract · Added November 12, 2019
Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organization's pharmacovigilance database of individual-case-safety-reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP ( = 68) and HA ( = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab-based therapy (monotherapy or combination with anti-programmed death-1 [PD-1]) was associated with earlier onset (median 23 vs. 47.5 days,  = .006) than anti-PD-1/programmed death ligand-1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. KEY POINTS: Immune-mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune-mediated hematologic toxicities.Further research is needed to define patient-specific risk factors and optimal management strategies for hematologic toxicities.
© AlphaMed Press 2019.
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19 MeSH Terms
Response to Anti-PD-1 in Uveal Melanoma Without High-Volume Liver Metastasis.
Johnson DB, Bao R, Ancell KK, Daniels AB, Wallace D, Sosman JA, Luke JJ
(2019) J Natl Compr Canc Netw 17: 114-117
MeSH Terms: Antineoplastic Agents, Immunological, Computational Biology, Gene Expression Profiling, Humans, Liver Neoplasms, Melanoma, Molecular Targeted Therapy, Neoplasm Staging, Prognosis, Programmed Cell Death 1 Receptor, Treatment Outcome, Uveal Neoplasms
Show Abstract · Added March 30, 2020
Uveal melanoma (UM) is an uncommon melanoma subtype with poor prognosis. Agents that have transformed the management of cutaneous melanoma have made minimal inroads in UM. We conducted a single-arm phase II study of pembrolizumab in patients with metastatic UM and performed bioinformatics analyses of publicly available datasets to characterize the activity of anti-PD-1 in this setting and to understand the mutational and immunologic profile of this disease. A total of 5 patients received pembrolizumab in this study. Median overall survival was not reached, and median progression-free survival was 11.0 months. One patient experienced a complete response after one dose and 2 others experienced prolonged stable disease (20% response rate, 60% clinical benefit rate); 2 additional patients had rapidly progressing disease. Notably, the patients who benefited had either no liver metastases or small-volume disease, whereas patients with rapidly progressing disease had bulky liver involvement. We performed a bioinformatics analysis of The Cancer Genome Atlas for UM and confirmed a low mutation burden and low rates of T-cell inflammation. Note that the lack of T-cell inflammation strongly correlated with pathway overexpression. Anti-PD-1-based therapy may cause clinical benefit in metastatic UM, seemingly more often in patients without bulky liver metastases. Lack of mutation burden and T-cell infiltration and overexpression may be factors limiting therapeutic responses. NCT02359851.
Copyright © 2019 by the National Comprehensive Cancer Network.
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12 MeSH Terms
Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8 T cells.
Gemta LF, Siska PJ, Nelson ME, Gao X, Liu X, Locasale JW, Yagita H, Slingluff CL, Hoehn KL, Rathmell JC, Bullock TNJ
(2019) Sci Immunol 4:
MeSH Terms: Animals, Antineoplastic Agents, Immunological, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Glucose, Glucose Transporter Type 1, Glycolysis, Hepatitis A Virus Cellular Receptor 2, Humans, Immunoglobulin G, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating, Melanoma, Mice, Inbred C57BL, Phosphopyruvate Hydratase, Programmed Cell Death 1 Receptor
Show Abstract · Added March 30, 2020
In the context of solid tumors, there is a positive correlation between the accumulation of cytotoxic CD8 tumor-infiltrating lymphocytes (TILs) and favorable clinical outcomes. However, CD8 TILs often exhibit a state of functional exhaustion, limiting their activity, and the underlying molecular basis of this dysfunction is not fully understood. Here, we show that TILs found in human and murine CD8 melanomas are metabolically compromised with deficits in both glycolytic and oxidative metabolism. Although several studies have shown that tumors can outcompete T cells for glucose, thus limiting T cell metabolic activity, we report that a down-regulation in the activity of ENOLASE 1, a critical enzyme in the glycolytic pathway, represses glycolytic activity in CD8 TILs. Provision of pyruvate, a downstream product of ENOLASE 1, bypasses this inactivity and promotes both glycolysis and oxidative phosphorylation, resulting in improved effector function of CD8 TILs. We found high expression of both enolase 1 mRNA and protein in CD8 TILs, indicating that the enzymatic activity of ENOLASE 1 is regulated posttranslationally. These studies provide a critical insight into the biochemical basis of CD8 TIL dysfunction.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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16 MeSH Terms
Small Cell Lung Cancer Transformation as a Mechanism of Resistance to PD-1 Therapy in KRAS-Mutant Lung Adenocarcinoma: A Report of Two Cases.
Iams WT, Beckermann KE, Almodovar K, Hernandez J, Vnencak-Jones C, Lim LP, Raymond CK, Horn L, Lovly CM
(2019) J Thorac Oncol 14: e45-e48
MeSH Terms: Adenocarcinoma of Lung, Aged, Antineoplastic Agents, Immunological, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Female, Humans, Lung Neoplasms, Mutation, Prognosis, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins p21(ras), Small Cell Lung Carcinoma
Added September 10, 2020
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MeSH Terms
PD-1 up-regulation on CD4 T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production.
Celada LJ, Kropski JA, Herazo-Maya JD, Luo W, Creecy A, Abad AT, Chioma OS, Lee G, Hassell NE, Shaginurova GI, Wang Y, Johnson JE, Kerrigan A, Mason WR, Baughman RP, Ayers GD, Bernard GR, Culver DA, Montgomery CG, Maher TM, Molyneaux PL, Noth I, Mutsaers SE, Prele CM, Peebles RS, Newcomb DC, Kaminski N, Blackwell TS, Van Kaer L, Drake WP
(2018) Sci Transl Med 10:
MeSH Terms: Adult, Aged, Animals, Bleomycin, CD4-Positive T-Lymphocytes, Cell Proliferation, Collagen Type I, Disease Models, Animal, Female, Fibroblasts, Gene Expression Regulation, Humans, Idiopathic Pulmonary Fibrosis, Interleukin-17, Male, Mice, Middle Aged, Programmed Cell Death 1 Receptor, RNA, Messenger, STAT3 Transcription Factor, Sarcoidosis, Th17 Cells, Transforming Growth Factor beta1, Up-Regulation
Show Abstract · Added March 26, 2019
Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1CD4 T cells with reduced proliferative capacity and increased transforming growth factor-β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4 T cells. PD-1 T helper 17 cells are the predominant CD4 T cell subset expressing TGF-β. Coculture of PD-1CD4 T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4 T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1CD4 T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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24 MeSH Terms