Autopsy of a patient with fatal Epstein–Barr virus-associated encephalitis after treatment with immune checkpoint inhibitors for advanced lung adenocarcinoma: a case report

Abstract Background Immunotherapy has revolutionized the treatment of malignant tumors. However, limited clinical data are available to report the efficacy of immune checkpoint inhibitors (ICIs) on Epstein-Barr virus-associated gastric carcinoma. Methods In this study, we report a case series of five patients with metastatic Epstein-Barr virus-associated gastric carcinoma who were treated with ICIs and to perform a pooled analysis of published cases to investigate the efficacy of ICIs in Epstein-Barr virus-associated gastric carcinoma patients. Results Between 2018 and 2020, five metastatic gastric cancer patients with EBV positivity who received PD-1 antibodies treatment were included in the analysis at the authors’ institution. Furthermore, we performed a pooled analysis of the contemporary literature. In our case series, two patients experienced partial response (PR); one patient achieved complete response (CR), whereas two patients had progression disease (PD), resulting an ORR of 60%. In the pooled analysis of all 36 patients, ORR was 48.6% (17/35). For the first line and later lines, it was 75% (3/4) and 45.2% (14/31) respectively. The ORR was 46.7% (14/30) for ICIs monotherapy and improved to 60% (3/5) by combination with chemotherapy. Conclusions These results demonstrated that an EBV-positive status was a reliable biomarker for immunotherapy in metastatic gastric cancer, especially for monotherapy. Immunotherapy combined with chemotherapy may be a better strategy, warranting further large-scale clinical trials for validation.

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Acute cerebellar ataxia due to Epstein-Barr virus under administration of an immune checkpoint inhibitor

BMJ Case Reports ◽

10.1136/bcr-2019-231520 ◽

2019 ◽

Vol 12 (12) ◽

pp. e231520 ◽

Cited By ~ 1

Author(s):

Hirotaka Saikawa ◽

Hiromi Nagashima ◽

Tetsuya Maeda ◽

Makoto Maemondo

Keyword(s):

Adverse Events ◽

Cerebellar Ataxia ◽

Immune Checkpoint ◽

Epstein Barr Virus ◽

Checkpoint Inhibitors ◽

Pulse Therapy ◽

Steroid Pulse ◽

Barr Virus ◽

Acute Cerebellar Ataxia ◽

Epstein Barr

A 71-year-old male patient with adenocarcinoma of the lung and contralateral lung metastasis under administration of pembrolizumab had symptoms of cerebellar ataxia. We suspected that the symptoms were immune-related adverse events (irAE), but the patient was subsequently diagnosed as cerebellitis due to Epstein-Barr virus (EBV) infection. After steroid pulse therapy, the symptoms of cerebellar ataxia improved immediately. Immune checkpoint inhibitors (ICI) can induce neurological adverse events and cause acute cerebellar ataxia. Initially, irAEs were suspected in this case. His clinical data suggested that reactivation of the virus had occurred because the ICI affected his immune system. This is the first report of a case of acute cerebellar ataxia due to EBV under administration of an ICI.

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Immune System Disorders, Cancer and Viral Infections: A New Treatment Opportunity for the Immune Checkpoint Inhibitors

Life ◽

10.3390/life11121400 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1400

Author(s):

Alejandro Olivares-Hernández ◽

Luis Figuero-Pérez ◽

José Pablo Miramontes-González ◽

Álvaro López-Gutiérrez ◽

Rogelio González-Sarmiento ◽

...

Keyword(s):

Immune System ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Viral Infections ◽

Checkpoint Inhibitors ◽

Nasopharyngeal Cancer ◽

Solid Tumours ◽

Barr Virus ◽

Epstein Barr ◽

New Treatment

The relationship between viral infections and cancer is well known and has been established for decades. Multiple tumours are generated from alterations secondary to viral infections 2 resulting from a dysregulation of the immune system in many cases. Certain causal relationships, such as that between the Epstein–Barr virus (EBV) in nasopharyngeal cancer or hepatitis C and B viruses in hepatocarcinoma, have been clearly established, and their implications for the prognosis and treatment of solid tumours are currently unknown. Multiple studies have evaluated the role that these infections may have in the treatment of solid tumours using immunotherapy. A possible relationship between viral infections and an increased response to immune checkpoint inhibitors (ICIs) has been established at a theoretical level in solid neoplasms, such as EBV-positive cavum cancer and human papillomavirus (HPV)-positive and oropharyngeal cancer. These could yield a greater response associated with the activation of the immune system secondary to viral infection, the consequence of which is an increase in survival in these patients. That is why the objective of this review is to assess the different studies or clinical trials carried out in patients with solid tumours secondary to viral infections and their relationship to the response to ICIs.

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Epigenetic alternate promoter utilization and association with PD-L1 expression in Epstein–Barr virus positive gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15509 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15509-e15509

Author(s):

Raghav Sundar ◽

Aditi Qamra ◽

Angie Lay Keng Tan ◽

Shenli Zhang ◽

Cedric Chuan Young Ng ◽

...

Keyword(s):

Gastric Cancer ◽

Immune Evasion ◽

Immune Checkpoint ◽

Epstein Barr Virus ◽

Checkpoint Inhibitors ◽

Primary Resistance ◽

Barr Virus ◽

Alternate Promoter ◽

Epstein Barr ◽

Gastric Cancer Patients

e15509 Background: We recently elicited the role of epigenetic promoter alterations as a mechanism of immune-evasion and primary resistance to immune checkpoint inhibition in gastric cancer. High prevalence of epigenetic modifications are known to occur in Epstein-Barr virus associated gastric cancer (EBVaGC). EBVaGC has high response rates to anti-PD-1 immune checkpoint inhibitors and is associated with high levels of PD-L1 expression. However, not all EBVaGC express PD-L1 and mechanisms that mediate these phenomena are unknown. Methods: We performed NanoString profiling and PD-L1 immunohistochemistry (using Dako PD-L1 IHC 22C3) on tissue from gastric cancer patients undergoing primary tumor resections at Samsung Medical Centre, South Korea. NanoString panel was designed for 90 recurrent somatic alternate promoter-related genes, and immune-related genes including PD-L1. EBV status was determined using EBV-encoded RNA in situ hybridization and categorized as EBVaGC and EBV-negative. Samples in the top-quartile of alternate promoter utilization were classified as APhigh and the remaining APlow. Results: A total of 272 samples (EBVaGC n = 79; EBV-negative n = 193) were included in this study. EBVaGC had significantly higher PD-L1 expression (p < 0.001) compared to EBV-negative samples. APhigh group (n = 67) consisted of 61 EBV-negative and 6 EBVaGC samples. EBVaGC APhigh tumors had significantly lower PD-L1 transcript expression compared to EBVaGC APlow tumors (p = 0.011, Wilcoxon-rank sum). Similar correlation was also found with PD-L1 IHC combined positive score (CPS)(median CPS score 1 vs 8, p = 0.047). There was a trend towards poorer survival for EBVaGC APhigh tumors (vs EBVaGC APlow; HR 0.23, 95% CI: 0.046 – 1.23, p = 0.087). EBV-negative APhigh tumors also had lower PD-L1 expression (vs EBV-negative APlow; p = 0.046, Wilcoxon-rank sum). Conclusions: Increased utilization of epigenetic alternate promoter isoforms correlates with lower transcriptomic and protein expression of PD-L1 in EBVaGC. Here we describe a potential mechanism of immune-evasion to explain low immune-infiltration and PD-L1 expression that occurs in a group of EBVaGC that is traditionally considered highly immunogenic.

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Current Treatment Landscape of Nasopharyngeal Carcinoma and Potential Trials Evaluating the Value of Immunotherapy

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djz044 ◽

2019 ◽

Vol 111 (7) ◽

pp. 655-663 ◽

Cited By ~ 8

Author(s):

Quynh Thu Le ◽

A Dimitrios Colevas ◽

Brian O’Sullivan ◽

Anne W M Lee ◽

Nancy Lee ◽

...

Keyword(s):

Clinical Trial ◽

Head And Neck Cancer ◽

Nasopharyngeal Carcinoma ◽

Immune Checkpoint Inhibitors ◽

Epstein Barr Virus ◽

Checkpoint Inhibitors ◽

Barr Virus ◽

Road Map ◽

Planning Meeting ◽

Epstein Barr

Abstract Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with a distinctive regional and racial prevalence. It is associated with Epstein-Barr virus infection and has a high propensity for regional and distant metastases, while it is very sensitive to radiation and chemotherapy. A common feature of Epstein-Barr virus-positive NPC is the dense infiltration of lymphocytes in the tumor stroma and positive programmed death-ligand 1 expression in tumor cells, making it an attractive target for immunotherapy, especially immune checkpoint inhibitors. As new immunotherapeutic agents are being rapidly adopted in many cancers, including head and neck cancer, the National Cancer Institute sponsored a clinical trial planning meeting to identify opportunities for developing phase II and III trials testing immunotherapy in different stages of NPC. The meeting started with the summary of the biology of the disease, current standards of care, and evidence of immunotherapy in this cancer. Three subcommittees were tasked to develop clinical trials: loco regionally advanced, nonmetastatic NPC; widely metastatic NPC; and either local recurrence after initial treatment or presenting with oligometastatic disease. This article summarizes the proceedings of this clinical trial planning meeting and provides a road map for future trials incorporating immune checkpoint inhibitors for therapeutic management of NPC. This road map, though specific for NPC, may also be applicable to other virally driven cancers that have similar ability to evade the host’s immune system.

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Chronic bullous disease of childhood following Epstein-Barr virus seroconversion: a case report

Clinical and Experimental Dermatology ◽

10.1046/j.1365-2230.1996.d01-194.x ◽

1996 ◽

Vol 21 (2) ◽

pp. 123-126

Author(s):

U. BALDARI ◽

A. ASCARI RACCAGNI ◽

B. CELLI ◽

M. GIOVANNA RIGHINI

Keyword(s):

Case Report ◽

Epstein Barr Virus ◽

Barr Virus ◽

Bullous Disease ◽

Epstein Barr

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Endoscopic endonasal approach to the cavernous sinus Epstein-Barr virus–positive B cell non-Hodgkin lymphoma in a child: case report

Child s Nervous System ◽

10.1007/s00381-021-05269-7 ◽

2021 ◽

Author(s):

Murat Kutlay ◽

Mükerrem Safalı ◽

Ömer Kartal ◽

Mehmet Ozan Durmaz ◽

Adem Doğan ◽

...

Keyword(s):

Case Report ◽

B Cell ◽

Hodgkin Lymphoma ◽

Epstein Barr Virus ◽

Endoscopic Endonasal Approach ◽

Endonasal Approach ◽

Endoscopic Endonasal ◽

Barr Virus ◽

Non Hodgkin Lymphoma ◽

Epstein Barr

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Fatal Epstein‐Barr virus‐associated hemophagocytic lymphohistiocytosis with virus‐infected T cells after pediatric multivisceral transplantation: A proof‐of‐concept case report

Pediatric Transplantation ◽

10.1111/petr.13961 ◽

2020 ◽

Author(s):

Masaki Yamada ◽

Seisuke Sakamoto ◽

Kenichi Sakamoto ◽

Hajime Uchida ◽

Seiichi Shimizu ◽

...

Keyword(s):

T Cells ◽

Case Report ◽

Hemophagocytic Lymphohistiocytosis ◽

Epstein Barr Virus ◽

Proof Of Concept ◽

Barr Virus ◽

Multivisceral Transplantation ◽

Epstein Barr

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Diffuse Cystic Metastases in the Lung after Nivolumab Treatment in a Patient with Non-Small Cell Lung Cancer: A Case Report

Case Reports in Oncology ◽

10.1159/000513426 ◽

2021 ◽

pp. 34-38

Author(s):

Satoshi Muto ◽

Yuki Ozaki ◽

Takuya Inoue ◽

Naoyuki Okabe ◽

Yuki Matsumura ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Lung Metastases ◽

Sialyl Lewis X ◽

Ground Glass ◽

Cystic Lesions ◽

Positron Emission ◽

Ground Glass Nodules

Although diffuse cysts in the lung can be found in many diseases, they are uncommon in metastatic lung adenocarcinoma. They are even more unusual after the administration of immune checkpoint inhibitors. A case of lung adenocarcinoma that developed diffuse cysts in the lungs during treatment with nivolumab is reported. The patient was a 60-year-old woman with postoperative recurrent lung adenocarcinoma in mediastinal lymph nodes and pleural dissemination. After first-line treatment with cisplatin, pemetrexed, and bevacizumab, computed tomography (CT) showed disease progression. Treatment was then switched to nivolumab. After 5 courses of nivolumab, CT showed multiple ground-glass nodules in her lungs. After 4 more courses of nivolumab, the ground-glass nodules increased in size, and cystic air spaces appeared in their centers. The patient did not have any symptoms. Laboratory tests showed no evidence of infection or nivolumab-induced pneumonitis. Sialyl Lewis X-i antigen increased, and positron emission tomography showed abnormal uptake of 18F-fluorodeoxyglucose in these lesions. Considering this evidence, the cystic lesions were diagnosed as multiple lung metastases. Various differential diagnoses should be considered when diffuse cystic lesions are found in the lungs after the administration of immune checkpoint inhibitors.

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