Developing an Ontology-Based Platform to Detect Serine Protease Involvement in BALT Lymphoma Patients with COVID-19 & Connect Them to Clinical Trials

Introduction:
Mucosal-associated lymphoid tissue (MALT) lymphomas are a rare form of non-Hodgkin lymphomas that develop from B cells and are often incidentally diagnosed. Although there exists a diverse number of subvariants, like bronchial-associated lymphoid tissue (BALT), their pathogenesis remains unclear. Given their rarity, heterogeneity, and positive prognosis, limited consensus exists on a standard treatment approach. Over the past few decades, several studies have demonstrated an association between coronaviral infections and BALT lymphoma, whereby serine protease binding disruptions and mutations, such as in SERPINE2, increase the risk of BALT, which could provide the basis for different treatment options for BALT lymphoma patients that otherwise could have been missed due to its rarity. The aim of this study was to use a computational approach to (1) validate and expand upon this relationship— specifically on the role of serine protease binding disruptions and its interplay between SARS-CoV-2/COVID-19 and the development of BALT lymphoma (2) identify applicable clinical trials based on this in-depth relationship.
Methods:
To address this, ontologies for serine proteolytic homeostasis were constructed utilizing keywords and abstracts from PubMed, which were then used with parsing and logical “OR” functions to generate search inputs for the European Bioinformatics Institute (EBI) COVID-19 ontology and , providing an effective link between search terms and clinical trials. Specifically, this method was utilized for and between input terms “BALT”, “lymphoma”, “serine protease”, as well as “heat shock protein” as an input for an embedded Serine Protease Inhibitor (SerPIn) subtype. The Heat Shock Protein 70 family and its more specific subtype Binding Immunoglobulin Protein (BiP) (a.k.a. , and ), were also manually identified as an alternative results marker for efficacy comparison.
Results:
Results showed that this platform successfully demonstrated a literary relationship between BALT lymphoma, serine proteases, and COVID-19. Most notably it identified a clinical trial on Adaptive Cellular Therapy, which aims to develop NK cells to target SARS-CoV-2 to better control this infection and potentially reduce BALT lymphoma onset. This strategy demonstrates a promising approach to automate the development of future ontologies to better characterize the pathogenesis between SARS-CoV-2, BALT lymphoma, and serine proteases, while also connecting patients to active clinical trials via .
Discussion:
This platform provides a foundation of genetic and proteomic information that can effectively be used to characterize disease pathogenesis of hematological malignancies— especially in the hematological rare disease space. Additionally, this platform can connect patients to active clinical trials and provide enrollment information. Future studies will continue to investigate the application of serine proteolytic homeostasis ontologies to BALT lymphoma and aid in better understanding its interplay with COVID-19, which can then be applied to develop targeted therapeutic solutions for critical BALT and MALT malignancies, while expanding its ability to connect patients to active clinical trials globally.