A5089491648- Cancer Immunotherapy and Biomarkers
- Histone Deacetylase Inhibitors Research
- Immune cells in cancer
- Immunotherapy and Immune Responses
- Fibroblast Growth Factor Research
- Cancer, Hypoxia, and Metabolism
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- CAR-T cell therapy research
- Click Chemistry and Applications
- Immune Cell Function and Interaction
- Peptidase Inhibition and Analysis
- vaccines and immunoinformatics approaches
- HIV/AIDS drug development and treatment
- Ferroptosis and cancer prognosis
- Cancer Research and Treatments
- Monoclonal and Polyclonal Antibodies Research
- Pancreatic and Hepatic Oncology Research
- Metabolism, Diabetes, and Cancer
- Eicosanoids and Hypertension Pharmacology
- Diet, Metabolism, and Disease
- Immune Response and Inflammation
- Colorectal Cancer Treatments and Studies
- Diet and metabolism studies
- Neuroscience and Neuropharmacology Research
Center for Cancer Research
2018-2022
Cancer Institute (WIA)
2019-2022
National Cancer Institute
2018-2022
AstraZeneca (Japan)
2022
AstraZeneca (United States)
2021-2022
National Institutes of Health
2004-2021
Moffitt Cancer Center
2021
Albany College of Pharmacy and Health Sciences
2017
Loyola University Chicago
2011-2016
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2004
Tumors evade host immune surveillance through multiple mechanisms, including the generation of a tumor microenvironment that suppresses effector function. Secretion TGFβ and upregulation checkpoint programmed cell death ligand-1 (PD-L1) are two main contributors to evasion progression. Here, we examined efficacy first-in-class bifunctional inhibitor, fusion protein M7824, comprising extracellular domain human TGFβRII (TGFβ Trap) linked C-terminus anti-PD-L1 heavy chain (αPD-L1). We...
<h3>Background</h3> Immunotherapy targeting PD-1/PD-L1 fails to induce clinical responses in most patients with solid cancers. N-803, formerly ALT-803, is an IL-15 superagonist mutant and dimeric IL-15RαSushi-Fc fusion protein complex that enhances CD8<sup>+</sup> T NK cell expansion function exhibits anti-tumor efficacy preclinical models. Previous vitro studies have shown increases PD-L1 expression, a negative regulator of function. Most reported administered N-803 intraperitoneally not...
Abstract Poorly inflamed carcinomas do not respond well to immune checkpoint blockade. Converting the tumour microenvironment into a functionally hub would extend clinical benefit of therapy larger proportion cancer patients. Here we show, by using comprehensive single-cell transcriptome, proteome, and cell analysis, that Entinostat, class I histone deacetylase inhibitor, facilitates accumulation necrosis-targeted recombinant murine immune-cytokine, NHS-rmIL12, in experimental mouse colon...
Myeloid-derived suppressor cells (MDSCs) are major negative regulators of immune responses in cancer and chronic infections. It remains unclear if regulation MDSC activity different conditions is controlled by similar mechanisms. We compared MDSCs mice with lymphocytic choriomeningitis virus (LCMV) infection. Chronic LCMV infection caused the development monocytic (M-MDSCs) but did not induce polymorphonuclear (PMN-MDSCs). In contrast, both populations were present models. An acquisition...
Checkpoint inhibitors targeting the PD-1/PD-L1 axis are promising immunotherapies shown to elicit objective responses against multiple tumor types, yet these agents fail benefit most patients with carcinomas. This highlights need develop effective therapeutic strategies increase blockade. Histone deacetylase (HDAC) in combination have provided preliminary evidence of anti-tumor effects. We investigated here whether exposure either natural killer (NK) cells and/or two different classes HDAC...
Background Immune checkpoint blockade (ICB) has achieved unprecedented success in treating multiple cancer types. However, clinical benefit remains modest for most patients with solid malignancies due to primary or acquired resistance. Tumor-intrinsic loss of major histocompatibility complex class I (MHC-I) and aberrations antigen processing machinery (APM) interferon gamma (IFN-γ) pathways have been shown play an important role ICB While a plethora combination treatments are being...
Abstract The ketogenic diet is a very low‐carbohydrate, high‐fat used to treat refractory epilepsy. We hypothesized that this may act by increasing expression of glutamic acid decarboxylase (GAD), the rate‐limiting enzyme in γ‐aminobutyric (GABA) synthesis. Thus, we evaluated brain GAD levels well‐established, seizure‐suppressing, rodent model diet. Because most effective when administered with modest (∼10%) calorie restriction, studied three groups animals: rats fed ad libitum standard rat...
Sprouty (Spry) proteins modulate the actions of receptor tyrosine kinases during development and tumorigenesis. Decreases in cellular levels Spry, especially Sprouty2 (Spry2), have been implicated growth progression tumors breast, prostate, lung, liver. During tumor growth, cells experience hypoxia. Therefore, we investigated how hypoxia modulates Spry proteins. Hypoxia elevated all four expressed isoforms HeLa cells. Amounts endogenous Spry2 LS147T HEP3B were also by Using as a prototype,...
Background Anti(α)-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy fails to provide durable clinical benefit for most patients with carcinoma. Recent studies suggested that strategies reduce immunosuppressive cells, promote systemic T-cell responses and lymphocyte trafficking the tumor microenvironment (TME) may improve efficacy. N-809 is a first-in-class bifunctional agent comprising interleukin (IL)-15 superagonist N-803 fused two αPD-L1 domains. Thus, can...
Immunotherapy has demonstrated clinical efficacy in subsets of patients with solid carcinomas. Multimodal therapies using agents that can affect different arms the immune system and/or tumor microenvironment (TME) might increase responses.We demonstrate entinostat, a class I histone deacetylase inhibitor, enhances antitumor IL15 superagonist N-803 plus vaccine 4T1 triple-negative breast and MC38-CEA colon murine carcinoma models. A comprehensive gene-expression analysis was performed...
Abstract Progressive tumor growth is associated with deficits in the immunity generated against antigens. Vaccines targeting neoepitopes have potential to address qualitative defects; however, additional mechanisms of immune failure may underlie progression. In such cases, patients would benefit from immune-oncology agents failure. This study explores identification MC38 colon carcinoma model by comparison normal DNA and RNA sequencing technology, as well neoepitope delivery both peptide-...
Breast tumors commonly harbor low mutational burden, PD-L1 expression, defective antigen processing/presentation, and an immunosuppressive tumor microenvironment (TME). In a malignancy mostly refractory to checkpoint blockade, there is unmet clinical need for novel combination approaches that increase immune infiltration control. Preclinical data have guided the development of this trial combining 1) BN-Brachyury (a poxvirus vaccine platform encoding associated brachyury), 2) bintrafusp alfa...
The α-subunits of hypoxia-inducible factors (HIF1α and HIF2α) promote transcription genes that regulate glycolysis cell survival growth. Sprouty2 (Spry2) is a modulator receptor tyrosine kinase signaling inhibits proliferation by number different mechanisms. Because the seemingly opposite actions HIFα subunits Spry2 on cellular processes, we investigated whether regulates levels HIF1α HIF2α proteins. In lines from types tumors in which decreased protein have been associated with poor...
Receptor Tyrosine Kinase (RTK) signaling plays a major role in tumorigenesis and normal development. Sprouty2 (Spry2) attenuates RTK inhibits processes such as angiogenesis, cell proliferation, migration survival, which are all upregulated tumors. Indeed cancers of the liver, lung, prostate breast, Spry2 protein levels markedly decreased correlating with poor patient prognosis shorter survival. Thus, it is important to understand how expression regulated. While prior studies have focused on...
Most monoclonal antibodies (MAbs), including immune checkpoint inhibitor MAbs, are delivered intravenously (i.v.) to patients. Recent clinical studies have demonstrated that some anti-PD1 MAbs may also be subcutaneously (s.c.), with outcomes similar of those obtained i.v.-delivered agents. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed the extracellular domain human transforming growth factor β receptor II (TGF-βRII or TGF-β "trap") fused heavy chain an IgG1 antibody...
Sprouty2 (Spry2) is an inhibitor of receptor tyrosine kinase signaling. Spry2 levels are decreased in cancers the breast, lung, prostate and liver, thereby permitting excessive signaling these pathologies. Furthermore, a decrease has been correlated with poor patient prognosis. In development tumor growth, cells experience hypoxic environment to which they adapt by up regulating transcription factors, Hypoxia Inducible Factors (HIFs). The HIFs composed beta subunit (HIF1β or aryl hydrocarbon...
Abstract The clinical promise of cancer immunotherapy relies on the immune system recognizing and eliminating tumor cells identified as non-self. However, microenvironment (TME) can greatly impede a targeted response via increasing immunosuppressive or hampering T NK cell maturation, recruitment, function through numerous pathways, including upregulation checkpoints such PD-L1. Hence, there is an unmet need to develop effective therapeutic strategies that reprogram TME restore recognition...
<h3>Background</h3> Immune checkpoint blockade (ICB) has achieved unprecedented success in treating multiple cancer types. However, clinical benefit remains modest for most patients with solid malignancies the majority having primary resistance to these therapies. Additionally, many that initially respond often acquire resistance. Tumor-intrinsic loss of MHC class I and aberrations interferon gamma (IFNγ) pathway have been shown play an important role ICB Entinostat, a HDAC inhibitor,...
Sprouty2 (Spry2) is an inhibitor of receptor tyrosine kinases (RTKs) and decreases in its levels have been documented breast, lung, liver, prostate cancer. Decreases Spry2 correlated with poor patient prognosis hepatocellular carcinoma (HCC). During tumor growth, cells experience hypoxic periods adapt to these by altering a variety cellular processes mainly through the Hypoxia Inducible transcription Factors (HIFs). HIFs are composed α subunit (HIF1α or HIF2α) β (HIF1β a.k.a. aryl...