Obi Lee Griffith

• PhD
• Professor (Assistant) at Washington University in St. Louis

The Drug-Gene Interaction database (DGIdb) mines existing resources that generate hypotheses about how mutated genes might be targeted therapeutically or prioritized for drug development. It provides an interface for searching lists of genes against a compendium of drug-gene interactions and potentially 'druggable' genes. DGIdb can be accessed at h...

Systemic chemotherapy in the adjuvant setting can cure breast cancer in some patients that would otherwise recur with incurable, metastatic disease. However, since only a fraction of patients would have recurrence after surgery alone, the challenge is to stratify high-risk patients (who stand to benefit from systemic chemotherapy) from low-risk pat...

An estimated 4% to 7% of the population will develop a clinically significant thyroid nodule during their lifetime. In many cases, preoperative diagnoses by needle biopsy are inconclusive. Thus, there is a clear need for improved diagnostic tests to distinguish malignant from benign thyroid tumors. The recent development of high-throughput molecula...

ORegAnno is an open-source, open-access database and literature curation system for community-based annotation of experimentally identified DNA regulatory regions, transcription factor binding sites and regulatory variants. The current release comprises 30 145 records curated from 922 publications and describing regulatory sequences for over 3853 g...

In this work, we present the Genome Modeling System (GMS), an analysis information management system capable of executing automated genome analysis pipelines at a massive scale. The GMS framework provides detailed tracking of samples and data coupled with reliable and repeatable analysis pipelines. The GMS also serves as a platform for bioinformati...

Neoantigen vaccines represent a promising immunotherapeutic approach against cancer. Ongoing work from our lab and others has facilitated neoantigen discovery and neoantigen-specific immunotherapy design that can lead to the elimination of established tumors without inducing toxicity. While early personalized neoantigen vaccine therapies for tumor-...

Background Neoantigen-targeting therapies including personalized vaccines have shown promise in the treatment of cancers, particularly when used in combination with checkpoint blockade therapy. At least 100 clinical trials involving these therapies have been initiated globally. Accurate identification and prioritization of neoantigens is crucial fo...

Background Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent dis...

Lymphopenia following chemoradiation for high grade gliomas (HGG) is common and is associated with decreased survival. NT-I7 (efineptakin alfa) is a long-acting analog of the lymphocyte pro-survival cytokine, interleukin-7. Our Phase I dose-escalation study of 19 patients with HGG demonstrated early elevations in CD4+ and CD8+ T cells in the first...

Multiple immune therapies such as CD19 CAR T-cells and bispecific antibodies are now approved for patients with relapsed/refractory large B-cell lymphoma (rrLBCL). The efficacy of these therapies is likely influenced by lymphoma microenvironment (LME) characteristics, but these have not been comprehensively characterized in rrLBCL. We performed sin...

People diagnosed with cancer and their formal and informal caregivers are increasingly faced with a deluge of complex information, thanks to rapid advancements in the type and volume of diagnostic, prognostic, and treatment data. This commentary discusses the opportunities and challenges that the society faces as we integrate large volumes of data...

Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results i...

Multiple therapies with immune mechanisms of action such as CAR T-cells and bispecific antibodies are now approved for relapsed/refractory large B-cell lymphoma (rrLBCL). The efficacy of these therapies is likely influenced by lymphoma microenvironment (LME) characteristics, but these have not been directly characterized in a comprehensive fashion....

Neoantigen targeting therapies including personalized vaccines have shown promise in the treatment of cancers. Accurate identification/prioritization of neoantigens is highly relevant to designing clinical trials, predicting treatment response, and understanding mechanisms of resistance. With the advent of massively parallel sequencing technologies...

While most dizygotic twins have a dichorionic placenta, rare cases of dizygotic twins with a monochorionic placenta have been reported. The monochorionic placenta in dizygotic twins allows in utero exchange of embryonic cells, resulting in chimerism in the twins. In practice, this chimerism is incidentally identified in mixed ABO blood types or in...

Kaposi Sarcoma (KS) is a complex tumor caused by KS-associated herpesvirus 8 (KSHV). Histological analysis reveals a mixture of “spindle cells”, vascular-like spaces, extravasated erythrocytes, and immune cells. In order to elucidate the infected and uninfected cell types in KS tumors, we examined skin and blood samples from twelve subjects by sing...

Spontaneous cancers in companion dogs are robust models of human disease. Tracking tumor-specific immune responses in these models requires reagents to perform species-specific single cell T cell receptor sequencing (scTCRseq). scTCRseq and integration with scRNA data have not been demonstrated on companion dogs with cancer. Here, five healthy dogs...

The monochorionic placenta in dizygotic twins allows in utero exchange of embryonic cells, resulting in chimerism in the twins. In practice, this chimerism is incidentally identified on mixed ABO blood types or in the presence of cells with a discordant sex chromosome. Here, we applied whole-genome sequencing to one triplet and one twin families to...

NK cells are innate lymphoid cells critical for mediating anti-tumor responses and are being advanced as a cancer immunotherapy. While conventional (c) NK cell-based therapies have been explored in clinical trials, challenges related to cancer target recognition, in vivo persistence, and functionality result in limited activity. To overcome these c...

The Drug–Gene Interaction Database (DGIdb, https://dgidb.org) is a publicly accessible resource that aggregates genes or gene products, drugs and drug–gene interaction records to drive hypothesis generation and discovery for clinicians and researchers. DGIdb 5.0 is the latest release and includes substantial architectural and functional updates to...

Objective The diversity of nomenclature and naming strategies makes therapeutic terminology difficult to manage and harmonize. As the number and complexity of available therapeutic ontologies continues to increase, the need for harmonized cross-resource mappings is becoming increasingly apparent. This study creates harmonized concept mappings that...

The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysi...

To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4⁺ T cell depletion. After classifying tumor cells based on detect...

Donor-derived follicular lymphoma after kidney transplant revealed by genomic profiling.

Working with therapeutic terminology in the field of medicine can be challenging due to both the number of ways terms can be addressed and the ambiguity associated with different naming strategies. A therapeutic concept can be identified across many facets from ontologies and vocabularies of varying focus, including natural product names, chemical...

Follicular lymphoma (FL) is clinically heterogeneous, with select patients tolerating extended watch-and-wait, while others require prompt treatment, suffer progression of disease within 24 months of treatment (POD24), and/or experience aggressive histologic transformation (t-FL). Because our understanding of the relationship between genetic altera...

Background Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autolog...

Since T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromis...

IL-12/15/18 activation induces natural killer (NK) cell differentiation into cytokine-induced memory-like (ML) NK cells with enhanced IFNγ and killing of tumor targets that is antigen independent, rendering them distinct from conventional (cNK) and CMV-induced adaptive NK cells. In leukemia patients, ML NK cells have an excellent safety profile and...

Our study aims are: (1) to evaluate phenotypically normal canine conjunctival and orbital tissue and tissue from canine lobular orbital adenomas (CLOAs) for the presence of viral genomic material and (2) phylogenetically classify detected DNA viruses to determine if a DNA virus is associated with CLOAs. A total of 31 formalin fixed paraffin embedde...

Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoanti...

Bladder cancer is the tenth most common cancer worldwide, accounting for over 500,000 new cancer cases and 200,000 cancer-related deaths per year. Depending on the degree of muscle invasiveness and disease spread at the time of diagnosis, 5-year survival rates can range from as high as 96% to as low as 6%. In recent years, use of checkpoint inhibit...

The comprehensive evaluation of somatic variants in cancer requires consensus interpretation of their potential clinical significance (diagnosis, prognosis, and treatment response) and oncogenicity. To aid precision medicine through public interpretations, a multifaceted collaborative effort is required to bring together a community, structured gui...

The immune milieu within tumors, consisting of diverse cell types including adaptive immune cells as well as macrophages, dendritic cells, natural killer and other innate immune cells, is critical to determining cancer outcome. However, the immune tumor microenvironment (TME) has been challenging to model, owing to inherent inter-species difference...

To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4+ T cell depletion. After classifying tumor cells based on detect...

Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools (www.regtools.org), a computationally efficient, free, and open-source software package designed to integrate somatic variants from genomic data with splice junctions from...

Neoantigens are peptides derived from non-synonymous mutations presented by human leukocyte antigens (HLAs), which are recognized by antitumour T cells1–14. The large HLA allele diversity and limiting clinical samples have restricted the study of the landscape of neoantigen-targeted T cell responses in patients over their treatment course. Here we...

With the increasing number of sequencing projects involving families, quality control tools optimized for family genome sequencing are needed. However, accurately quantifying contamination in a DNA mixture is particularly difficult when genetically related family members are the sources. We developed TrioMix, a maximum likelihood estimation (MLE) f...

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capabil...

Background The primary target of T-cell responses to cancer cells are peptides derived from non-synonymous mutations presented by HLA. However, the large diversity of HLA alleles and restricted availability of clinical samples has limited the study of the antigenic determinants recognized by T cells (termed neoepitopes) at the scale needed for a la...

Cancer is often hereditary which would require sequencing of the proband as well as the parents. Before detecting and analyzing cancer mutations, quality control of the family genome sequencing is needed to ensure integrity of the data. However, accurate detection and quantification of the contamination in a DNA mixture is particularly difficult wh...

Neoantigens are novel peptide sequences resulting from somatic mutations in tumors that upon loading onto major histocompatibility complex (MHC) molecules allow recognition by T cells. Accurate neoantigen identification is thus critical for designing cancer vaccines and predicting response to immunotherapies. Neoantigen prioritization relies on cor...

Malignant cells of Hodgkin lymphoma (HL), Hodgkin and Reed-Sternberg (HRS) cells, are rare and surrounded by a non-neoplastic infiltrate. Tumor microenvironment (TME) expression profiling has been successful but remains incomplete for HRS cells. We examined gene expression in two HL and one follicular lymphoma (FL) sample using single nuclei RNA se...

Somatic cancer variant oncogenicity holds great importance. Evidence demonstrating oncogenic or benign variant effects may have clinical implications. For example, in colorectal cancer, an activating KRAS mutation will preclude EGFR inhibitor treatment, but guidelines may allow EGFR administration if KRAS mutation is benign.Therefore it is clear th...

There are many ways to represent the same molecular variation which can lead to variation ambiguity. Translating between different formats (e.g., HGVS, VCF, gnomAD) and centralized authoritative identifiers (e.g., ClinGen Allele Registry, ClinVar, dbSNP) for a single variation can be labor intensive. These problems can lead to the inability to easi...

Mutations in histone H3 (oncohistones) result in widespread epigenetic dysregulation and are increasingly recognized as oncogenic events in many different cancer types. In particular, H3.1/3 K27M and G34R/V oncohistones define a subset of highly aggressive pediatric gliomas arising in the midline ('diffuse midline glioma, H3 K27-altered') and cereb...

Functional genomics, which involves massively parallel experimentation on a large set of variants (e.g., saturation mutagenesis of missense mutations) from a single gene, leveraging next generation sequencing, has emerged as an active area to gain large datasets. Visualization and analysis requires specialized tools that work with large volumes of...

Genomic aberrations disrupting fibroblast growth factor receptors (FGFR) signalling have been implicated in several human cancers and are an emerging focus of targeted therapies. While routine large-scale sequencing has resulted in the identification of numerous variants in the FGFR genes, these variants have never been uniformly and comprehensivel...

Brain and central nervous system tumors are the most common form of solid tumor cancers and the second most common cancer overall among children. Although advances have been made in understanding the genomics of childhood brain tumors, the role of copy number alterations (CNAs) has not been fully characterized. While genomes of childhood brain tumo...

BCR::ABL1-like B-lymphoblastic leukemia/lymphoma (B-ALL) is a neoplasm of precursor B cells and a subtype of high-risk B-ALL that exhibits a gene expression profile similar to that of BCR::ABL1-positive B-ALL while lacking the BCR::ABL1 fusion protein. Instead, it is characterized by somatic variants in a variety of cytokine receptor and kinase enc...

CIViC, the Clinical Interpretation of Variants in Cancer knowledgebase (www.civicdb.org), has provided structured data and an open-access curation interface to enable scientists and other community stakeholders to curate variant information from published literature since 2014. Since then, CIViC has continued to evolve to incorporate new community...

The Drug-Gene Interaciton Database (DGIdb, www.dgidb.org) is a publicly accessible resource that aggregates over 100,000 drug-gene interaction claims across 30 interaction types aid both researchers and clinicians in identifying associations between genes of interest and available therapeutics. By incorporating peer-reviewed data sources and public...

Canine models of cancers are increasingly being recognized as valuable tools in the exploration of disease. Further it is becoming increasingly apparent that a deeper understanding of the interaction between the immune system and tumorigenesis may yield promising new insights and therapies. To date however, tools and methods to investigate the inte...

Multiple guidelines and standards have been issued globally to aid in Next Generation Sequencing (NGS) variant interpretation. The AMP/ASCO/CAP, ACMG/AMP, and ESMO published guidelines are incorporated into cancer NGS reports in different ways around the globe. The Variant Interpretation for Cancer Consortium Virtual Molecular Tumor Board (VICC-VMT...

Mantle Cell Lymphoma (MCL) is a B-cell non-Hodgkin Lymphoma that currently has poor prognosis and few effective treatments. This project was intended to explore the variants that characterize MCL, and potentially identify targets for novel treatments. The patient cohort included 28 individuals who contributed lymph node biopsies and matched skin no...

Circulating tumor DNA (ctDNA) in peripheral blood can predict prognosis and therapeutic response for triple-negative breast cancer (TNBC) patients. However, most approaches use large comprehensive panels of commonly mutated genes. This study assessed the use of custom micro-panels for tracking disease and predicting clinical outcomes for patients w...

FMS-like tyrosine kinase 3 (FLT3) encodes a receptor tyrosine kinase with key roles in the survival, proliferation, and differentiation of hematopoietic cells. FLT3 variants are the most common alterations in acute myeloid leukemia (AML), occurring in approximately 30% of all AML cases. Routine screening for FLT3 variants in AML patients is recomme...

Neoantigens are tumor-specific peptides presented on the cell surface by MHC that can be recognized by the adaptive immune system. Personalized immunotherapies, such as cancer vaccines, rely on neoantigen prediction to identify sequences that can activate T cells to recognize and destroy the tumor. The majority of cancer vaccine trials have utilize...

Gene fusions involving the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are well established oncogenic drivers in a broad range of pediatric and adult tumors, and important diagnostic and therapeutic markers predicting response to FDA approved kinase inhibitors. Accurate interpretation of the clinical significance of NTRK-f...

TheraPy is a Python software package that constructs searchable normalized concepts for drugs and other therapeutics to assist in harmonization of biomedical knowledge. Because a therapy may variably be referred to by brand or generic names, experimental terms, and database IDs, it is challenging to match concepts across different sources. TheraPy...

Interpretation of the clinical significance of somatic variants in cancer remains a major challenge in cancer diagnosis, prognosis, and treatment decisions. The Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG) facilitates the development of data curation guidelines and standards to determine the clinical signif...

Canine malignant melanoma (CMM) mimics human melanoma in invasiveness, metastatic behavior, and limited survival. Novel immunotherapies could target CMM neoantigen expression to dissect mechanisms of success and failure in a naturally occurring model of cancer. Tools to predict and validate canine MHC I presentation of neoantigens must be optimized...