Successful management of Epstein‑Barr virus‑associated severe checkpoint inhibitor‑related pneumonitis: A case report

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Abstract

A novel current treatment, immunotherapy, is normally effective for pulmonary lymphoepithelial carcinoma (pLELC). However, it is frequently accompanied by responses such as immune checkpoint inhibitor-associated pneumonitis (CIP), a rare immune adverse reaction that may be fatal in severe cases. pLELC is known to be linked to Epstein-Barr virus (EBV), while associations between EBV and CIP in clinical settings have rarely been reported. A 57-year-old male patient with pLELC presented at our hospital with cough, expectoration, fever and dyspnea following his third course of immunotherapy at another hospital. Diagnosis of grade 4 CIP was confirmed. Simultaneously, a rapid increase in the EBV titer and response of CIP to corticosteroids were observed. The corticosteroids and antiviral drugs were then increased. In spite of his severe condition, the patient recovered within eight days. After discontinuing antiviral drugs, chest computed tomography indicated rapid lesion progression and significantly increased bilateral multiple metastases. To our knowledge, the present study was the first to report a case of CIP caused by EBV during immune checkpoint inhibitor treatment. It indicates that EBV may be associated with CIP development. As immunotherapy has off-target effects, clinicians should remain aware of combined corticosteroids and antivirals in similar cases.

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Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

Nicholas McGranahan, Andrew J. S. Furness, Rachel Rosenthal … (2016)

One contributing factor in antitumor immunity is the repertoire of neoantigens created by genetic mutations within tumor cells. Like the corresponding mutations, these neoantigens show intratumoral heterogeneity. Some are present in all tumor cells (clonal), and others are present in only a fraction of cells (subclonal). In a study of lung cancer and melanoma, McGranahan et al. found that a high burden of clonal tumor neoantigens correlated with improved patient survival, an increased presence of tumor-infiltrating lymphocytes, and a durable response to immunotherapy. Science , this issue p. [Related article:] 1463 Analysis of the cellular ancestry of tumor neoantigens can predict which are most likely to induce an immune response. As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8 + tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.

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The 2021 WHO Classification of Lung Tumors: Impact of advances since 2015

Andrew G Nicholson, Ming S. Tsao, Mary Beasley … (2021)

The 2021 WHO Classification of Thoracic Tumours was published earlier this year, with classification of lung tumors being one of the chapters. The principles remain those of using morphology first, supported by immunohistochemistry, and then molecular techniques. In 2015, there was particular emphasis on using immunohistochemistry to make classification more accurate. In 2021, there is greater emphasis throughout the book on advances in molecular pathology across all tumor types. Major features within this edition are (1) broader emphasis on genetic testing than in the 2015 WHO Classification; (2) a section entirely dedicated to the classification of small diagnostic samples; (3) continued recommendation to document percentages of histologic patterns in invasive nonmucinous adenocarcinomas, with utilization of these features to apply a formal grading system, and using only invasive size for T-factor size determination in part lepidic nonmucinous lung adenocarcinomas as recommended by the eighth edition TNM classification; (4) recognition of spread through airspaces as a histologic feature with prognostic significance; (5) moving lymphoepithelial carcinoma to squamous cell carcinomas; (6) update on evolving concepts in lung neuroendocrine neoplasm classification; (7) recognition of bronchiolar adenoma/ciliated muconodular papillary tumor as a new entity within the adenoma subgroup; (8) recognition of thoracic SMARCA4-deficient undifferentiated tumor; and (9) inclusion of essential and desirable diagnostic criteria for each tumor.

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PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses.

Maria Themeli, D Fedorov, Vadim Fedorov … (2013)

T cell therapies have demonstrated long-term efficacy and curative potential for the treatment of some cancers. However, their use is limited by damage to bystander tissues, as seen in graft-versus-host disease after donor lymphocyte infusion, or "on-target, off-tumor" toxicities incurred in some engineered T cell therapies. Nonspecific immunosuppression and irreversible T cell elimination are currently the only means to control such deleterious responses, but at the cost of abrogating therapeutic benefits or causing secondary complications. On the basis of the physiological paradigm of immune inhibitory receptors, we designed antigen-specific inhibitory chimeric antigen receptors (iCARs) to preemptively constrain T cell responses. We demonstrate that CTLA-4- or PD-1-based iCARs can selectively limit cytokine secretion, cytotoxicity, and proliferation induced through the endogenous T cell receptor or an activating chimeric receptor. The initial effect of the iCAR is temporary, thus enabling T cells to function upon a subsequent encounter with the antigen recognized by their activating receptor. iCARs thus provide a dynamic, self-regulating safety switch to prevent, rather than treat, the consequences of inadequate T cell specificity.

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Author and article information

Journal

Journal ID (nlm-ta): Exp Ther Med

Journal ID (iso-abbrev): Exp Ther Med

Journal ID (publisher-id): ETM

Title: Experimental and Therapeutic Medicine

Publisher: D.A. Spandidos

ISSN (Print): 1792-0981

ISSN (Electronic): 1792-1015

Publication date Collection: May 2023

Publication date (Electronic): 29 March 2023

Publication date PMC-release: 29 March 2023

Volume: 25

Issue: 5

Electronic Location Identifier: 222

Affiliations

Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China

Author notes

Correspondence to: Professor Chengzhi Zhou, Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong 510120, P.R. China doctorzcz163.com hh_zhang@ 123456szu.edu.cn

^*Contributed equally

Abbreviations: pLELC, pulmonary lymphoepithelial carcinoma; EBV, Epstein-Barr virus; PD-L1, programmed cell death ligand 1; irAEs, immune-related adverse events; CIP, checkpoint inhibitor-associated pneumonitis; CMV, cytomegalovirus; CT, computed tomography; IT, induced type; TCR, T-cell receptor

Article

Publisher ID: ETM-25-5-11921

DOI: 10.3892/etm.2023.11921

PMC ID: 10133792

SO-VID: 9f2c161d-50eb-4ef7-8299-df66d14d5776

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 19 September 2022

Date accepted : 08 March 2023

Funding

Funding: This study was supported by grants from the State Key Laboratory of Respiratory Disease-The Independent project (grant no. SKLRD-Z-202206) and Wu Jieping Medical Foundation (grant no. 320.6750.2020-19-8).

Successful management of Epstein‑Barr virus‑associated severe checkpoint inhibitor‑related pneumonitis: A case report

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IET: COVID-19 related research

Most cited references 16

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

The 2021 WHO Classification of Lung Tumors: Impact of advances since 2015

PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses.

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