A5000755157- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- Cancer Cells and Metastasis
- CAR-T cell therapy research
- Cutaneous Melanoma Detection and Management
- Epigenetics and DNA Methylation
- Immune cells in cancer
- Peptidase Inhibition and Analysis
- Melanoma and MAPK Pathways
- RNA Interference and Gene Delivery
- Cancer Research and Treatments
- vaccines and immunoinformatics approaches
- Tryptophan and brain disorders
- Cancer Genomics and Diagnostics
- T-cell and B-cell Immunology
- Inflammasome and immune disorders
- Polyomavirus and related diseases
- Ferroptosis and cancer prognosis
- Reproductive System and Pregnancy
- Nanoplatforms for cancer theranostics
- TGF-β signaling in diseases
- Cancer Diagnosis and Treatment
- interferon and immune responses
- Bladder and Urothelial Cancer Treatments
Duke Medical Center
2016-2025
Duke University
2014-2025
Duke Cancer Institute
2016-2023
Duke University Hospital
2023
Cancer Institute (WIA)
2016-2021
University of Virginia Medical Center
2021
Piedmont International University
2021
Galveston College
2021
Texas Medical Board
2021
Monash Medical Centre
2017
PURPOSE Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the polyomavirus. Clinical trials of programmed death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall (OS) data are limited. PATIENTS AND METHODS In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy aMCC...
Abstract Immune checkpoint inhibitors, including antibodies that block programmed cell death protein-1 (PD-1) and PD-L1, have transformed the management of many cancers. However, majority patients primary or acquired resistance to these immunotherapies. There is a significant unmet need for predictive biomarkers can reliably identify who derive clinically meaningful response from PD-1/PD-L1 blockade. High tumor mutational burden (TMB-H) has shown promise as biomarker in lung cancer, but...
An in-depth understanding of immune escape mechanisms in cancer is likely to lead innovative advances immunotherapeutic strategies. However, much remains unknown regarding these and how they impact immunotherapy resistance. Using several preclinical tumor models as well clinical specimens, we identified a mechanism whereby CD8+ T cell activation response programmed death 1 (PD-1) blockade induced ligand 1/NOD-, LRR-, pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling...
Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification CD63 as specific surface marker, we demonstrate that mature regulatory (mregDCs) migrate tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 cell differentiation. Transcriptional metabolic studies...
The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable driving regulatory T-cell (Treg) differentiation. Further studies have implicated DCs in promoting carcinogenesis preclinical models. molecular mechanisms underlying establishment immune tolerance by this DC are poorly understood, and methods which developing cancers can co-opt subvert surveillance currently unknown. This work demonstrates that...
Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, which tumors manipulate and function tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) its shed extracellular domain (sTGFBR3) regulate signaling maintain...
Background Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors MCC 3-year survival, explore the effects salvage therapies in patients experiencing initial non-response or progression after response stable disease following first-line pembrolizumab therapy...
<h3>Background</h3> Checkpoint inhibitor immunotherapy is becoming an effective treatment modality for increasing number of malignancies. As a result, autoinflammatory side-effects are also being observed more commonly in the clinic. We currently unable to predict which patients will develop severe toxicities associated with these regimens. <h3>Case presentation</h3> present patient stage IV melanoma that developed rapid onset autoimmune type 1 diabetes (T1D) response combination ipilimumab...
Although anti-PD-1 therapy has improved clinical outcomes for select patients with advanced cancer, many exhibit either primary or adaptive resistance to checkpoint inhibitor immunotherapy. The role of the tumor stroma in development these mechanisms inhibitors remains unclear. We demonstrated that pharmacologic inhibition TGFβ signaling pathway synergistically enhanced efficacy anti-CTLA-4 immunotherapy but failed augment anti-PD-1/PD-L1 responses an autochthonous model BRAFV600E melanoma....
Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of challenges and opportunities facing melanoma research community patients with melanoma. Since then, remarkable progress has been made on both basic clinical fronts. However, incidence, recurrence, death rates for remain unacceptably high significant remain. Hence, MRF Scientific Advisory Council Breakthrough Consortium, a group that includes clinicians scientists, reconvened to facilitate intensive discussions...
While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway diminished T cell infiltration; however, activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling evasion. In study, we show that proximal mediators of the anti-PD-1 resistance, and pharmacologic inhibition ligand supports efficacy by reversing dendritic...
<h3>Background</h3> Epacadostat is a potent inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. We present phase results from 1/2 clinical study epacadostat in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, advanced melanoma (NCT01604889). <h3>Methods</h3> Only 1, open-label portion was conducted, per sponsor’s decision to terminate early based on changing treatment landscape favoring exploration programmed cell death...
Immune checkpoint blockade (ICB) therapies have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, sex-specific differences response to ICB been observed, with males receiving a greater benefit from than females, although the mechanism or mechanisms underlying this difference are unknown. Mining published transcriptomic data sets, we determined that ICBs is influenced by functionality of intratumoral macrophages. This puts into...
The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome–heat shock protein 70 (HSP70) signaling axis is triggered by CD8 + T cell cytotoxicity contributes to the development of adaptive resistance anti–programmed death 1 (PD-1) immunotherapy recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into tumor microenvironment. Here, we demonstrate that NLRP3-HSP70 also drives accumulation PMN-MDSCs distant lung tissues in a...
While blockade of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) T cell regulatory receptor has become a commonly utilized strategy in management advanced melanoma, many questions remain regarding use this agent patient populations with autoimmune disease. We present case involving treatment stage IV melanoma and ulcerative colitis (UC) anti-CTLA-4 antibody immunotherapy. Upon initial treatment, developed grade III requiring tumor necrosis factor-alpha (TNF-α) blocking therapy, however...
The APOBEC family of cytidine deaminases is one the most common endogenous sources mutations in human cancer. Genomic studies tumors have found that mutational signatures are enriched HER2 subtype breast cancer and associated with immunotherapy response diverse types. However, direct consequences mutagenesis on tumor immune microenvironment not been thoroughly investigated. To address this, we developed syngeneic murine mammary models inducible expression APOBEC3B. We activity induced...
Abstract Despite the potency of dendritic cells (DC) as antigen-presenting for priming adaptive immunity, DC-based cancer vaccines have been largely insufficient to effectively reduce tumor burden or prevent progression in most patients. To enhance vaccines, we used combination a synthetic ligand-inducible CD40 receptor (iCD40) along with Toll-like receptor-4 (TLR-4) ligation human monocyte-derived DCs. The iCD40 permits targeted, reversible activation vivo, potentially bypassing essential...