10 results on '"Charlene M. Fares"'
Search Results
2. Immune checkpoint inhibitor induced thyroid dysfunction is a frequent event post-treatment in NSCLC
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Benjamin Bachrach, Nawal M. Yessuf, Maria A. Velez, Paige M. Brodrick, Sarah R. Rettinger, Edward B. Garon, Philippe Rochigneux, Jackson P. Lind-Lebuffe, Jonathan W. Goldman, Aaron Lisberg, Jaklin Gukasyan, Debory Y. Li, Charlene M. Fares, Tristan Grogan, Wisdom O. Akingbemi, Nanruoyi Zhou, Amy L. Cummings, University of California [Los Angeles] (UCLA), University of California (UC), Providence Hlth & Serv, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ROCHIGNEUX, Philippe
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Oncology ,Cancer Research ,Lung Neoplasms ,Anti-PD-(L)1 therapy ,endocrine system diseases ,[SDV]Life Sciences [q-bio] ,Thyroid Gland ,non-small cell lung cancer (NSCLC) ,Immune checkpoint inhibitor ,Non-small cell lung cancer ,Carcinoma, Non-Small-Cell Lung ,Non-Small-Cell Lung ,Lung ,Immune Checkpoint Inhibitors ,ComputingMilieux_MISCELLANEOUS ,Cancer ,Incidence (epidemiology) ,Lung Cancer ,Thyroid ,Thyroid dysfunction ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,6.1 Pharmaceuticals ,Cohort ,hormones, hormone substitutes, and hormone antagonists ,Pulmonary and Respiratory Medicine ,endocrine system ,medicine.medical_specialty ,Clinical Sciences ,Oncology and Carcinogenesis ,Article ,Immune system ,Immune related adverse events ,Clinical Research ,Internal medicine ,medicine ,Humans ,Endocrine system ,Oncology & Carcinogenesis ,Adverse effect ,Retrospective Studies ,business.industry ,Carcinoma ,Evaluation of treatments and therapeutic interventions ,Retrospective cohort study ,medicine.disease ,Good Health and Well Being ,business - Abstract
Introduction Thyroid dysfunction is the most frequent endocrine immune related adverse event (irAE) in non-small cell lung cancer (NSCLC), typically arising 3–6 months into immune checkpoint inhibitor (ICI) therapy, but arising after ICI cessation, in some cases. Due to limited post-treatment adverse event reporting requirements on ICI trials, the incidence of ICI-induced thyroid dysfunction arising after therapy is unclear. We investigated ICI-induced thyroid dysfunction in a cohort of 294 NSCLC patients, with a specific focus on the post-treatment setting. Methods Retrospective analysis of ICI-induced thyroid dysfunction (clinically acted upon or laboratory only) was performed in 294 UCLA NSCLC patients treated 2012–2018. Clinically acted upon thyroid dysfunction was defined as thyroid diagnosis documentation and/or thyroid medication administration. Laboratory only dysfunction was defined as abnormal thyroid labs in the absence of clinical action. Timing of thyroid dysfunction relative to ICI treatment and thyroid monitoring patterns were also assessed. Results 82% (241/294) of ICI treated NSCLC patients had thyroid labs during treatment. Of these 241 patients, 13% (31/241) had clinically acted upon thyroid dysfunction prior to, 8% (18/241) during, and 4% (9/241) after ICI. Most patients, 66% (159/241), did not have thyroid labs after ICI, but in the 53 patients with labs and no prior clinical dysfunction, 17% (9/53) developed clinical dysfunction after ICI. In these 9 patients, median time from ICI initiation to dysfunction was 253 days. Two patients with post-treatment laboratory only dysfunction were observed. Conclusions ICI-induced thyroid dysfunction arising post-treatment appears more common than previously appreciated, warranting additional evaluation.
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- 2021
3. Association of PD-L1 expression by immunohistochemistry and gene microarray with molecular subtypes of ovarian tumors
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Curtis D Chin, I. P. Shintaku, Jianyu Rao, Hsiao-Wang Chen, Gottfried E. Konecny, Charlene M. Fares, and Maira P. Campos
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0301 basic medicine ,Oncology ,Pathology ,medicine.medical_specialty ,Tumor microenvironment ,Microarray ,business.industry ,medicine.disease ,Pathology and Forensic Medicine ,03 medical and health sciences ,Serous fluid ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Ovarian carcinoma ,Internal medicine ,Gene expression ,medicine ,Immunohistochemistry ,DNA microarray ,business ,Ovarian cancer - Abstract
Identifying patients who respond to immune checkpoint blockade (ICB) is a significant challenge in oncology. While PD-L1 expression by immunohistochemistry (IHC) is the current diagnostic gold standard for patient selection, it nevertheless does not capture all patients who may respond to ICB. Recent gene expression studies in high-grade serous ovarian carcinoma have defined an immunoreactive molecular subtype that has a measurable difference in patient survival compared with non-immunoreactive subtypes, but no studies have yet demonstrated its impact on predicting response to ICB. As a step toward establishing the predictive value of gene expression classifiers in ICB, we assessed the relationship between PD-L1 IHC and molecular subtypes of ovarian epithelial cancer. This was done by analyzing a total of 93 tissue specimens from patients with stage III and IV disease, and comparing PD-L1 IHC with gene expression by Agilent microarrays using TCGA-defined subtypes. We showed that ovarian tumors with elevated IHC PD-L1 expression are most strongly associated with immunoreactive subtype as compared with other molecular subtypes, reaching statistical significance against differentiated (Dunn’s test, 33.39, p = 0.0003) and mesenchymal (39.63, p
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- 2020
4. Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?
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Charles G. Drake, Eliezer M. Van Allen, Siwen Hu-Lieskovan, Charlene M. Fares, and James P. Allison
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0301 basic medicine ,T-Lymphocytes ,medicine.medical_treatment ,Drug resistance ,Lymphocyte Activation ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,Immunity ,Neoplasms ,Biomarkers, Tumor ,Tumor Microenvironment ,Humans ,Medicine ,Antigen Presentation ,business.industry ,Cancer ,General Medicine ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Gastrointestinal Microbiome ,Blockade ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,business ,Signal Transduction - Abstract
The emergence of immune checkpoint blockade therapies over the last decade has transformed cancer treatment in a wide range of tumor types. Unprecedented and durable clinical responses in difficult-to-treat cancer histologies have been observed. However, despite these promising long-term responses, the majority of patients fail to respond to immune checkpoint blockade, demonstrating primary resistance. Additionally, many of those who initially respond to treatment eventually experience relapse secondary to acquired resistance. Both primary and acquired resistance are a result of complex and constantly evolving interactions between cancer cells and the immune system. Many mechanisms of resistance have been characterized to date, and more continue to be uncovered. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve clinical outcomes. This review will discuss the landscape of immune checkpoint blockade response data, different resistance mechanisms, and potential therapeutic strategies to overcome resistance.
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- 2019
5. Osimertinib as neoadjuvant therapy in a patient with stage IIIA non-small cell lung cancer: a case report
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Caroline Y. Chen, Daniel Sanghoon Shin, and Charlene M. Fares
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Oncology ,Lung Neoplasms ,medicine.medical_treatment ,Case Report ,Disease ,0302 clinical medicine ,Non-small cell lung cancer ,Surgical oncology ,Carcinoma, Non-Small-Cell Lung ,Osimertinib ,030212 general & internal medicine ,Epidermal growth factor receptor ,Stage (cooking) ,Non-Small-Cell Lung ,Lung ,Neoadjuvant therapy ,Cancer ,Aniline Compounds ,biology ,Lung Cancer ,General Medicine ,Neoadjuvant Therapy ,5.1 Pharmaceuticals ,6.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Medicine ,Development of treatments and therapeutic interventions ,Neoadjuvant ,Tyrosine kinase ,medicine.medical_specialty ,Clinical Trials and Supportive Activities ,03 medical and health sciences ,Clinical Research ,General & Internal Medicine ,Internal medicine ,Case report ,medicine ,Humans ,Protein Kinase Inhibitors ,Tyrosine kinase inhibitors ,Acrylamides ,Other Medical and Health Sciences ,business.industry ,Carcinoma ,Evaluation of treatments and therapeutic interventions ,respiratory tract diseases ,Clinical trial ,Good Health and Well Being ,Mutation ,biology.protein ,business - Abstract
Introduction Tyrosine kinase inhibitors (TKI) targeting epidermal growth factor receptor (EGFR) are approved for use in metastatic non-small cell lung cancer (NSCLC). Case presentation Here we present a case of a African American patient with stage IIIA NSCLC treated with osimertinib in the neoadjuvant setting with concurrent radiation, followed by resection. The patient remains disease-free 4 months after surgery. Conclusion This case report suggests that osimertinib may be effective as neoadjuvant therapy in resectable stage III disease. Additionally, we provide a summary of previous case reports and ongoing clinical trials for neoadjuvant EGFR inhibition in stage III NSCLC patients.
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- 2020
6. Mutational landscape influences immunotherapy outcomes among patients with non-small-cell lung cancer with human leukocyte antigen supertype B44
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Debory Li, Jesse M. Zaretsky, Antoni Ribas, Amy L. Cummings, Benjamin Bachrach, Jaklin Gukasyan, Alex A. T. Bui, Aaron Lisberg, Steven M. Dubinett, Wisdom O. Akingbemi, Nicholas Hornstein, Jonathan W. Goldman, Gemalene Sunga, Henry Lu, Edward B. Garon, Maura Rossetti, Tristan Grogan, James M. Carroll, David Elashoff, Zorawar S. Noor, and Charlene M. Fares
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Cancer Research ,Lung Neoplasms ,Somatic cell ,medicine.medical_treatment ,Population ,Glutamic Acid ,Human leukocyte antigen ,HLA-B44 Antigen ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,education ,Lung cancer ,Melanoma ,education.field_of_study ,business.industry ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Blockade ,Oncology ,HLA-B Antigens ,Mutation ,Cancer research ,business - Abstract
Human leukocyte antigen (HLA)-B has been recognized as a major determinant of discrepancies in disease outcomes, and recent evidence indicates a role in immune checkpoint blockade (ICB) efficacy. The B44 supertype, which features an electropositive binding pocket that preferentially displays peptides with negatively charged amino acid anchors, is associated with improved survival in ICB-treated melanoma. Yet this effect was not seen in ICB-treated non-small-cell lung cancer (NSCLC). Here we show that mutations leading to glutamic acid substitutions occur more often in melanoma than NSCLC based on mutational landscape. We additionally show stratifying B44 based on the presence of somatic mutations that lead to negatively charged glutamic acid anchors identifies patients with NSCLC with an ICB benefit similar to that seen in melanoma. We anticipate these findings could improve assessment of HLA-related outcomes and prediction of ICB benefit in those with B44, representing approximately half of the world’s population. Garon and colleagues demonstrate that the association of HLA supertype B44 with response to immune checkpoint blockade in melanoma but not NSCLC is related to differential mutational features that influence HLA binding of neoepitopes.
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- 2020
7. Biomarkers that may predict response to immunotherapy in ovarian malignancies
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Gottfried E. Konecny, Curtis D Chin, Jianyu Rao, and Charlene M. Fares
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,B7-H1 Antigen ,Immune system ,Internal medicine ,medicine ,Biomarkers, Tumor ,Tumor Microenvironment ,Humans ,Immune Checkpoint Inhibitors ,Ovarian Neoplasms ,Tumor microenvironment ,Predictive marker ,business.industry ,Obstetrics and Gynecology ,Cancer ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Clinical trial ,Female ,Neoplasm Recurrence, Local ,business ,Ovarian cancer - Abstract
Purpose of review Immune checkpoint blockade (ICB) is a promising area of cancer therapeutic research. Therapies targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) mechanism of tumor immune evasion have resulted in durable responses in many difficult-to-treat tumor types. While these inhibitors are being actively investigated in clinical trials for ovarian cancer, most patients fail to respond to initial treatment with immune therapy. This review focuses on biomarkers for predicting response to treatment, and discusses clinical trials using ICB for recurrent ovarian cancer. Recent findings While PD-L1 detection by immunohistochemistry (IHC) is approved as a companion or complementary diagnostic in some cancers, there are many limitations with its use as a predictive marker. Recent research has explored biomarkers beyond PD-L1 that assess for somatic mutations, immune cell infiltrate, and gene signatures. Summary With improved understanding of the tumor microenvironment and genomic classifications of ovarian tumors, new diagnostics and biomarkers that supplement conventional IHC may help predict response to therapy.
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- 2019
8. Association of homologous recombination deficiency in ovarian cancer with neoantigen load and expression of immune checkpoints
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Gottfried E. Konecny, Kathleen Fenerty, and Charlene M. Fares
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Cancer Research ,business.industry ,Treatment options ,medicine.disease ,Immune checkpoint ,Blockade ,Immune system ,Oncology ,medicine ,Cancer research ,Single agent ,Ovarian cancer ,Homologous Recombination Deficiency ,business ,Objective response - Abstract
5536 Background: Immune checkpoint blockade (ICB) is being explored as a treatment option in ovarian cancer, but objective response rates for single agent ICB are modest at around 10-15%. Validated biomarkers are needed to predict which patients will respond to ICB. BRCA mutations and homologous recombination deficiency (HRD) status are the only validated integral biomarkers in ovarian cancer. HRD tumors exhibit defective DNA repair mechanisms that promote increased mutational burden, which we postulate may correlate with higher neoantigen load and increased expression of targetable immune checkpoints. Methods: The Cancer Genome Atlas (TCGA) ovarian cancer dataset was evaluated and previously published, well annotated samples were obtained for HRD status. HLA type was determined with OptiType. Nonsynonymous mutations were annotated with Ensembl VEP. pVAC-Seq using NetMHCpan algorithm predicted neoepitopes 9 amino acids in length for MHC class I, reporting only those with a predicted IC50 less than 500 nM. Immune checkpoint gene expression counts were normalized with TCGAbiolinks. Correlation between HRD status and neoantigen load was assessed by Wilcoxon test. After log2 transformation, Wilcoxon tests evaluated for association between HRD status and expression of immune checkpoints. The relationship between HRD status and PD-L1 protein abundance with reverse phase protein array was measured. Results: Data from 154 HRD positive and 198 HRD negative tumors were analyzed. HRD positive status correlated with higher neoantigen load (p = 0.038) and increased expression of the immune checkpoints CTLA4 (p = 0.024), TIGIT (p = 0.027), and PVR (p = 0.002), but not PD-L1 (p = 0.238), LAG3 (p = 0.583), HVEM (p = 0.805), GAL9 (p = 0.750), NECTIN2 (p = 0.874), VSIG3 (p = 0.438), PSGL1 (p = 0.205) or VISTA (p = 0.531). TIM3 (p = 0.064) and B7H3 (p = 0.052) both demonstrated a trend towards increased expression in HRD tumors. Interestingly, HRD status showed a negative association with PVRIG (p = 0.028). There was no association between PD-L1 protein abundance and HRD status. Conclusions: HRD positive ovarian tumors demonstrate higher neoantigen load than HRD negative tumors, as well as increased expression of certain immune checkpoints. This supports the hypothesis that increased neoantigen load leads to compensatory induction of immune checkpoints, and suggests that HRD status may predict response to ICB, particularly to drugs that target CTLA4, TIGIT, PVR, TIM3 and B7H4.
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- 2021
9. Low Concordance of Patient-Reported Outcomes With Clinical and Clinical Trial Documentation
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James M. Carroll, Annette L. Stanton, Amy L. Cummings, Timothy Williamson, Edward B. Garon, Charlene M. Fares, Marshall L. Spiegel, Matthew K. Theisen, and Krikor Bornazyan
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Adult ,Male ,medicine.medical_specialty ,Concordance ,Vital signs ,MEDLINE ,Context (language use) ,Documentation ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Original Report ,030212 general & internal medicine ,Patient Reported Outcome Measures ,Adverse effect ,Aged ,Clinical Trials as Topic ,business.industry ,Medical record ,Standard treatment ,General Medicine ,Middle Aged ,humanities ,Clinical trial ,030220 oncology & carcinogenesis ,Physical therapy ,Female ,business - Abstract
Purpose Health care research increasingly relies on assessment of data extracted from electronic medical records (EMRs). Clinical trial adverse event (AE) logs and patient-reported outcomes (PROs) are sources of data often available in the context of specific research projects. The aim of this study was to evaluate the extent of data concordance from these sources. Patients and Methods Patients enrolled in clinical trials or receiving standard treatment for lung cancer (n = 62) completed validated questionnaires on physical and psychological symptoms at up to three assessment points. Temporally matched documentation was extracted from EMR notes and, for clinical trial participants (n = 41), AE logs. Evaluated data included symptom assessment, vital signs, medication logs, and laboratory values. Agreement (positive, negative) and Cohen’s κ coefficients were calculated to assess concordance of symptoms among sources, with PROs considered the gold standard. Results Patient-reported weight loss correlated significantly with clinical measurements ( t = 2.90; P = .02), and average number of PROs correlated negatively with albumin concentration, supporting PROs as the gold standard. Comparisons of PROs versus EMR yielded poor concordance across 11 physical symptoms, anxiety, and depressive symptoms (all κ < 0.40). Providers under-reported the presence of each symptom in the EMR compared with PROs. AE logs showed similarly poor concordance with PROs (all κ < 0.40, except shortness of breath). Negative agreement among sources was higher than positive agreement for all symptoms except pain. Conclusion There was poor concordance between EMR notes and AE logs with PROs. Findings suggest that EMR notes and AE logs may not be reliable sources for capturing physical and psychological symptoms experienced by patients with lung cancer, supporting use of PRO assessments in oncology practices.
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- 2019
10. Prevalence of human leukocyte antigen-B27 supertype in the context of positively charged neoepitopes and association with PD-L1 as an immune escape mechanism
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Wisdom O. Akingbemi, Jaklin Gukasyan, Charlene M. Fares, Amy L. Cummings, Nawal M. Yessuf, Deborah J.L. Wong, Aaron Lisberg, Matthew K. Theisen, Edward B. Garon, Jackson P. Lind-Lebuffe, Chantal Ava Barksdale, Paige M. Brodrick, and Debory Y. Li
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Cancer Research ,biology ,business.industry ,Mechanism (biology) ,Immune escape ,Binding pocket ,Context (language use) ,Human leukocyte antigen ,Immune checkpoint ,Blockade ,Oncology ,PD-L1 ,Immunology ,biology.protein ,Medicine ,business - Abstract
3083 Background: Recent evidence suggests efficacy of immune checkpoint blockade may be influenced by human leukocyte antigen (HLA)-B. HLA-B27 supertype has an electronegative binding pocket which favorably binds and displays neoepitopes harboring positively charged amino acids (AAs). Based on immune surveillance, we postulate that B27 tumors that have favorable neoepitopes should face negative selective pressure, and B27 tumors with favorable neoepitopes that develop could be more likely to upregulate immune escape mechanisms. Here we evaluate the relationship between prevalence of B27 and positively charged neoepitopes and assess association between positively charged neoepitopes and expression of PD-L1. Methods: TCGA datasets from head and neck squamous cell (HNSC), lung squamous cell (LUSC), and melanoma (SKCM) patients were evaluated. HLA alleles were determined with OptiType and supertype was based on 2008 criteria. Nonsynonymous mutations were annotated with Ensembl VEP and VAtools. pVAC-Seq using NetMHCpan algorithm predicted neoepitopes 9 AAs in length. Favorable B27 neoepitopes were defined as those having new positively charged AA substitutions (H/K/R) from negative or uncharged wildtype AAs. RNA-seq data for the PD-L1 gene were normalized on transcripts per million and log2 transformed. Linear regression tests were performed between PD-L1 gene expression values and fraction of nonsynonymous mutations resulting in neoepitopes with new positively charged AAs in patients with B27. Results: Data from 497 HNSC, 494 LUSC, and 468 SKCM patients were analyzed. B27 was observed in 20.1%, 23.2%, and 26.5% of HNSC, LUSC, and SKCM patients, respectively, with a significant difference seen between HNSC and SKCM by chi-square test (χ² = 5.14, p = .023). Of new charged AAs resulting from nonsynonymous mutations, 76.3% in HNSC, 74.0% in LUSC, and 72.0% in SKCM were positively charged (p < .05 between all histologies, paired t-tests). In B27 patients, association between PD-L1 gene expression and fraction of neoepitopes with new positively charged AAs was seen in HNSC (r = 0.25 p = .036) and SKCM (r = 0.30 p = .007), but not LUSC (r = -0.12 p = .296). Conclusions: With increasing fraction of positively charged neoepitopes, a decrease in prevalence of B27 was observed, suggesting improved binding and immune elimination of tumors with favorable neoepitopes. In B27 tumors that develop despite having favorable neoepitopes, upregulation of PD-L1 could be a putative mechanism to evade immune detection.
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- 2020
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