A5022285180- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Virus-based gene therapy research
- Pancreatic and Hepatic Oncology Research
- vaccines and immunoinformatics approaches
- Single-cell and spatial transcriptomics
- Viral Infectious Diseases and Gene Expression in Insects
- Viral Infections and Immunology Research
- Animal Virus Infections Studies
- Virology and Viral Diseases
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Cancer Genomics and Diagnostics
- Glioma Diagnosis and Treatment
- Early Childhood Education and Development
- Herpesvirus Infections and Treatments
- RNA Interference and Gene Delivery
- Space Exploration and Technology
- Cancer Research and Treatments
- Hepatocellular Carcinoma Treatment and Prognosis
- Peptidase Inhibition and Analysis
- Pancreatitis Pathology and Treatment
- SARS-CoV-2 and COVID-19 Research
- interferon and immune responses
University of Baltimore
2022-2024
Johns Hopkins University
2021-2024
Sidney Kimmel Comprehensive Cancer Center
2021-2024
Johns Hopkins Medicine
2021-2024
Convergence
2023
Bloomberg (United States)
2021-2023
Mayo Clinic in Arizona
2016-2022
Sidney Kimmel Cancer Center
2021
WinnMed
2019-2020
Mayo Clinic
2019-2020
Oncolytic viruses (OVs) encoding a variety of transgenes have been evaluated as therapeutic tools to increase the efficacy chimeric antigen receptor (CAR)–modified T cells in solid tumor microenvironment (TME). Here, using systemically delivered OVs and CAR immunocompetent mouse models, we defined mechanism by which can potentiate cell against models melanoma glioma. We show that stimulation native (TCR) with viral or virally encoded epitopes gives rise enhanced proliferation, CAR-directed...
Abstract The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified cells, to solid tumors requires combinatorial strategies overcome immune suppression associated with the tumor microenvironment. Here we test whether inflammatory nature oncolytic viruses and their ability remodel microenvironment may help recruit potentiate functionality CAR cells. Contrary our hypothesis, VSVmIFNβ infection is attrition murine EGFRvIII cells in a...
Abstract APOBEC3B, an anti-viral cytidine deaminase which induces DNA mutations, has been implicated as a mediator of cancer evolution and therapeutic resistance. Mutational plasticity also drives generation neoepitopes, prime anti-tumor T cells. Here, we show that overexpression APOBEC3B in tumors increases resistance to chemotherapy, but simultaneously heightens sensitivity immune checkpoint blockade murine model melanoma. However, the vaccine setting, APOBEC3B-mediated mutations...
Neoadjuvant immunotherapy is thought to produce long-term remissions through induction of antitumor immune responses before removal the primary tumor. Tertiary lymphoid structures (TLS), germinal center-like that can arise within tumors, may contribute establishment immunological memory in this setting, but understanding their role remains limited. Here, we investigated contribution TLS immunity hepatocellular carcinoma (HCC) treated with neoadjuvant immunotherapy. We found induced formation...
Personalized cancer vaccines aim to activate and expand cytotoxic antitumor CD8+ T cells recognize kill tumor cells. However, the role of CD4+ cell activation in clinical benefit these is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for pancreatic line Panc02, which activates tumor-specific but required combinatorial checkpoint modulators achieve therapeutic efficacy. To determine effects neoantigen-specific activation, we generated (PancVAX2)...
Abstract Background: The development of pancreatic ductal adenocarcinoma (PDAC) from the first driver event takes >10 years, providing a unique window opportunity for early interception. As frequent alteration identified in both PDAC and premalignancy, mutant KRAS (mKRAS) has emerged as potential target immune-based interception strategies individuals at high risk developing cancer. Methods: This is single-arm, open-label, second-in-human phase I study pooled synthetic long peptide...
Systemic viroimmunotherapy activates endogenous innate and adaptive immune responses against both viral tumor antigens. We have shown that therapy with vesicular stomatitis virus (VSV) engineered to express a tumor-associated antigen antigen-specific adoptively transferred T cells (adoptive cell therapy, ACT) in vivo generate effective therapy. The overall goal of this study was phenotypically characterize the response VSV+ACT use information gained rationally improve combination observed...
Measles virus (MeV), like all viruses of the order Mononegavirales, utilizes a complex consisting genomic RNA, nucleoprotein, RNA-dependent RNA polymerase, and polymerase cofactor, phosphoprotein (P), for transcription replication. We previously showed that recombinant MeV does not express another viral protein, C, has severe replication deficiencies, including steeper gradient than parental generation defective interfering RNA. This is attenuated in vitro vivo However, how C protein...
Abstract In our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNβ), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNβ-escape tumors predictably express a point-mutated CSDE1 P5S form the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor VSV replication disrupting viral transcription. Given time, VSV-IFNβ evolves compensatory mutation in P / M Inter-Genic...
Tumor cells frequently evade applied therapies through the accumulation of genomic mutations and rapid evolution. In case oncolytic virotherapy, understanding mechanisms by which cancer develop resistance to infection lysis is critical development more effective viral-based platforms. Here, we identify APOBEC3 as an important factor that restricts potency vesicular stomatitis virus (VSV). We show VSV B16 murine melanoma upregulated in IFN-β-dependent manner, was responsible for evolution...
Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which turn opportunities for cure. Despite advances locoregional approaches, there is currently no role incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to grossly positive resection margin preventing local recurrence. Incomplete was performed mice bearing syngeneic flank Panc02 tumors, leaving 1 mm rim adherent the muscle bed. A previously...
Antitumor T-cell responses raised by first-line therapies such as chemotherapy, radiation, tumor cell vaccines, and viroimmunotherapy tend to be weak, both quantitatively (low frequency) qualitatively affinity). We show here that T cells recognize tumor-associated antigens can directly kill if used at high effector-to-target ratios. However, when these tumor-reactive were present suboptimal ratios, direct T-cell-mediated killing was reduced the ability of evolve away from a coapplied therapy...
<h3>Background</h3> Immunotherapy has shown remarkable clinical promise in the treatment of various types cancers. However, benefits derive from a highly inflammatory mechanism action. This presents unique challenges for use pediatric brainstem tumors including diffuse intrinsic pontine glioma (DIPG), since treatment-related inflammation could cause catastrophic toxicity. Therefore, goal this study was to investigate whether inflammatory, immune-based therapies are likely be too dangerous...
Diffuse midline glioma, formerly DIPG (diffuse intrinsic pontine glioma), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated (i) whether direct delivery adenovirus-expressing cluster differentiation (CD)40 ligand (Ad-CD40L) to tumors would induce immune-mediated clearance and (ii) if so, therapy be associated a manageable toxicity due inflammation in brainstem.
Abstract Background: Oncogenic mutations in KRAS are expressed up to 90% of pancreatic ductal adenocarcinomas (PDAC). Vaccination against mutant (mKRAS) is thus a promising approach as an off-the-shelf immunotherapeutic treatment for PDAC. We developed mKRAS peptide vaccine targeting 6 common (G12V, G12A, G12C, G12R, G12D, or G13D (NCT04117087). evaluated the specific T cell response induced by vaccination combination with immune checkpoint inhibitors (ICIs) patients resected Materials and...
Enhancing the immunogenicity of tumor-associated antigens would represent a major advance for anti-tumor vaccination strategies. Here, we investigated structure-directed antigen destabilization as strategy to improve degradation, immunogenic epitope presentation, and T cell activation against vesicular stomatitis virus (VSV)-encoded tumor antigen. We used crystal structure model ovalbumin identify charge-disrupting amino acid mutations that were predicted decrease stability protein. One...
Abstract The evolution of pancreatic ductal adenocarcinoma (PDAC) from tumor initiation to metastases requires years decades, providing a window opportunity for the prevention premalignant progression. One first genetic mutations occur early in development is KRAS, an oncogene that expressed by over 90% PDACs. KRAS (mKRAS) are attractive targets as they recurrent hot–spot drivers by, and drive growth all PDAC cells. Preclinical data provide compelling evidence targeting mKRAS proteins using...
Abstract A common precursor of pancreatic adenocarcinoma (PDAC) are microscopic lesions, termed intraepithelial neoplasia (or PanIN). These lesions initiated at least a decade before overt PDAC forms, thus providing large window opportunity to modulate the immune microenvironment significant pro-carcinogenic signals prevail. To best inform strategies for interception these it is critical understand quantity and spatial localization lymphoid compartment recruited PanINs compared PDAC. Here,...
Abstract Background: Oncogenic mutations in KRAS (mKRAS) are expressed up to 90% of pancreatic ductal adenocarcinomas (PDAC) therefore representing a promising immunotherapeutic target. We developed pooled mKRAS peptide vaccine targeting the 6 most common PDAC: G12V, G12A, G12C, G12R, G12D, or G13D (NCT04117087). In phase I study, we evaluated mKRAS-specific T cell responses raised by when given combination with immune checkpoint inhibitors PDAC patients following resection and adjuvant...
Abstract Background: Tertiary lymphoid structures (TLS) are ectopic follicles that arise in non-lymphoid tissue. TLS may contribute to response immune checkpoint blockade (ICB) solid tumors, but understanding of the life cycle these structures, particularly circumstances their resolution and functional contribution this stage adaptive response, remains incomplete. Methods: We employed a multi-omics approach evaluate tumors patients with hepatocellular carcinoma (HCC) treated neoadjuvant ICB...
T cell immune tolerance is established in part through the activity of Auto-immune Regulator (AIRE) transcription factor medullary Thymic Epithelial Cells (mTEC) thymus. AIRE induces expression SELF peripheral tissue-specific antigens for presentation to naïve cells promote activation/deletion potentially autoreactive cells. We show, first time our knowledge, that tumors mimic role mTEC evade rejection. Thus, by expressing a broad range epitopes against which minimal functional reactivities...
Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly cancer with low tumor mutational burden that leads to the generation of few neo-epitopes derived from mutated genes can be recognized by cytotoxic T cells. The immunosuppressive microenvironment PDAC comprises suppressive cell populations include myeloid cells, associated fibroblast subpopulations, and regulatory cells reduce infiltration function. We have developed murine personalized vaccine enhance function against PDAC, PancVAX...