Publications by authors named "Judy R Van Beijnum"

Chimeric antigen receptor (CAR) T cell therapy presents significant results, especially for the treatment of hematologic malignancies. However, there are limitations and challenges to be overcome to achieve similar success for the treatment of solid tumors. These challenges involve selection of the target, infiltration into the tumor microenvironment and maintenance of functionality.

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Exposure to nanoparticles (NPs) in pregnancy is increasingly linked to adverse effects on embryo-fetal development and health later in life. However, the developmental toxicity mechanisms of NPs are largely unknown, in particular potential effects on the placental secretome, which orchestrates many developmental processes pivotal for pregnancy success. This study demonstrates extensive material- and pregnancy stage-specific deregulation of placental signaling from a single exposure of human placental explants to physiologically relevant concentrations of engineered (silica (SiO) and titanium dioxide (TiO) NPs) and environmental NPs (diesel exhaust particles, DEPs).

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The interest in finding new targets in the tumor microenvironment for anti-cancer therapy has increased rapidly over the years. More specifically, the tumor-associated blood vessels are a promising target. We recently found that the intermediate filament protein vimentin is externalized by endothelial cells of the tumor vasculature.

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It was recently shown that targeting extracellular vimentin (eVim) is safe and effective in preclinical models. Here, we report the safety and efficacy in client-owned dogs with spontaneous bladder cancer of CVx1, an iBoost technology-based vaccine targeting eVim in combination with COX-2 inhibition. This was a single-arm prospective phase 1/2 study with CVx1 in 20 client-owned dogs with spontaneous UC which involved four subcutaneous vaccinations with CVx1 at 2-week intervals for induction of antibody titers, followed by maintenance vaccinations at 2-month intervals.

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Purpose: Ongoing angiogenesis renders the tumor endothelium unresponsive to inflammatory cytokines and interferes with adhesion of leukocytes, resulting in escape from immunity. This process is referred to as tumor endothelial cell anergy. We aimed to investigate whether anti-angiogenic agents can overcome endothelial cell anergy and provide pro-inflammatory conditions.

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Poor immunogenicity of critical epitopes can hamper vaccine efficacy. To boost immune recognition of non- or low-immunogenic antigens, we developed a vaccine platform based on the conjugation of a target protein to a chimeric designer peptide (CDP) of bacterial origin. Here, we exploited this immune Boost (iBoost) technology to enhance the immune response against the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein.

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Extensive angiogenesis is a characteristic feature in the synovial tissue of rheumatoid arthritis (RA) from a very early stage of the disease onward and constitutes a crucial event for the development of the proliferative synovium. This process is markedly intensified in patients with prolonged disease duration, high disease activity, disease severity, and significant inflammatory cell infiltration. Angiogenesis is therefore an interesting target for the development of new therapeutic approaches as well as disease monitoring strategies in RA.

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Anti-angiogenic cancer therapies possess immune-stimulatory properties by counteracting pro-angiogenic molecular mechanisms. We report that tumor endothelial cells ubiquitously overexpress and secrete the intermediate filament protein vimentin through type III unconventional secretion mechanisms. Extracellular vimentin is pro-angiogenic and functionally mimics VEGF action, while concomitantly acting as inhibitor of leukocyte-endothelial interactions.

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For successful application of chimeric antigen receptor (CAR) T cell therapy in solid tumors, major hurdles have to be overcome. CAR T cells have to cross the vascular barrier, which is hampered by the anergic state of the tumor vasculature, characterized by suppressed levels of leukocyte adhesion molecules on the endothelium. Additional immunosuppressive mechanisms in the solid tumor microenvironment can affect infiltration, activity and persistence of CAR T cells.

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Immune checkpoint inhibitors have revolutionized medical oncology, although currently only a subset of patients has a response to such treatment. A compelling body of evidence indicates that anti-angiogenic therapy has the capacity to ameliorate antitumour immunity owing to the inhibition of various immunosuppressive features of angiogenesis. Hence, combinations of anti-angiogenic agents and immunotherapy are currently being tested in >90 clinical trials and 5 such combinations have been approved by the FDA in the past few years.

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Clear cell renal cell carcinoma (ccRCC) is characterized by high histone deacetylase (HDAC) activity triggering both cell motility and the development of metastasis. Therefore, there is an unmet need to establish innovative strategies to advance the use of HDAC inhibitors (HDACIs). We selected a set of tyrosine kinase inhibitors (TKIs) and HDACIs to test them in combination, using the validated therapeutically guided multidrug optimization (TGMO) technique based on experimental testing and in silico data modeling.

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The current standard of care for colorectal cancer (CRC) is a combination of chemotherapeutics, often supplemented with targeted biological drugs. An urgent need exists for improved drug efficacy and minimized side effects, especially at late-stage disease. We employed the phenotypically driven therapeutically guided multidrug optimization (TGMO) technology to identify optimized drug combinations (ODCs) in CRC.

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Combined application of multiple therapeutic agents presents the possibility of enhanced efficacy and reduced development of resistance. Definition of the most appropriate combination for any given disease phenotype is challenged by the vast number of theoretically possible combinations of drugs and doses, making extensive empirical testing a virtually impossible task. We have used the streamlined-feedback system control (s-FSC) technique, a phenotypic approach, which converges to optimized drug combinations (ODC) within a few experimental steps.

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The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored.

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Patients with advanced colorectal cancer (CRC) still depend on chemotherapy regimens that are associated with significant limitations, including resistance and toxicity. The contribution of tyrosine kinase inhibitors (TKIs) to the prolongation of survival in these patients is limited, hampering clinical implementation. It is suggested that an optimal combination of appropriate TKIs can outperform treatment strategies that contain chemotherapy.

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T cells armed with a chimeric antigen receptor, CAR T cells, have shown extraordinary activity against certain B lymphocyte malignancies, when targeted towards the CD19 B cell surface marker. These results have led to the regulatory approval of two CAR T cell approaches. Translation of this result to the solid tumor setting has been problematic until now.

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Background: Crenolanib is a tyrosine kinase inhibitor targeting PDGFR-α, PDGFR-β and Fms related tyrosine kinase-3 (FLT3) that is currently evaluated in several clinical trials. Although platelet-derived growth factor receptor (PDGFR) signalling pathway is believed to play an important role in angiogenesis and maintenance of functional vasculature, we here demonstrate a direct angiostatic activity of crenolanib independently of PDGFR signalling.

Methods: The activity of crenolanib on cell viability, migration, sprouting, apoptosis and mitosis was assessed in endothelial cells, tumour cells and fibroblasts.

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CD99 (MIC2; single-chain type-1 glycoprotein) is a heavily O-glycosylated transmembrane protein (32 kDa) present on leukocytes and activated endothelium. Expression of CD99 on endothelium is important in lymphocyte diapedesis. CD99 is a diagnostic marker for Ewing's Sarcoma (EWS), as it is highly expressed by these tumors.

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Background: In a genomic screen for determinants of the tumour vasculature, we identified insulin receptor (INSR) to mark the tumour endothelium. As a functional role for insulin/INSR in cancer has been suggested and markers of the tumour endothelium may be attractive therapeutic targets, we investigated the role of INSR in angiogenesis.

Methods: In a genomic screen for determinants of the tumour vasculature we identified insulin receptor to mark the tumour endothelium.

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The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations.

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The induction of an antibody response against self-antigens requires a conjugate vaccine technology, where the self-antigen is conjugated to a foreign protein sequence, and the co-application of a potent adjuvant. The choice of this foreign sequence is crucial as a very strong antibody response towards it may compromise the anti-self immune response. Here, we aimed to optimize the conjugate design for application of vaccination against the tumor vasculature, using two different approaches.

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Tumor angiogenesis is characterized by deregulated gene expression in endothelial cells (EC). While studies until now have mainly focused on overexpressed genes in tumor endothelium, we here describe the identification of transcripts that are repressed in tumor endothelium and thus have potential suppressive effects on angiogenesis. We identified nineteen putative angiosuppressor genes, one of them being bromodomain containing 7 (BRD7), a gene that has been assigned tumor suppressor properties.

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