A5019230153- CAR-T cell therapy research
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Radiopharmaceutical Chemistry and Applications
- Immune Cell Function and Interaction
- Cancer Research and Treatments
- Immune cells in cancer
- Extracellular vesicles in disease
- MicroRNA in disease regulation
- T-cell and B-cell Immunology
- Nanoplatforms for cancer theranostics
- RNA Interference and Gene Delivery
- Cancer, Hypoxia, and Metabolism
- Angiogenesis and VEGF in Cancer
- Glycosylation and Glycoproteins Research
- Cell Adhesion Molecules Research
- Virus-based gene therapy research
- Advanced Biosensing Techniques and Applications
- Liver physiology and pathology
- Chemokine receptors and signaling
- Neuroblastoma Research and Treatments
- Air Quality Monitoring and Forecasting
- Characterization and Applications of Magnetic Nanoparticles
- T-cell and Retrovirus Studies
QUIRIS Healthcare
2021-2023
National Cancer Institute
2014-2020
Center for Cancer Research
2016-2020
National Institutes of Health
2016-2020
Universidad de Navarra
2010-2015
Clinica Universidad de Navarra
2011-2015
Navarre Institute of Health Research
2015
Bipar
2014
Chartered Institute of Management Accountants
2013-2014
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
2013
Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) essential the response to therapy with anti-CD137 anti-PD-1 mAbs. mice failed prime an endogenous CTL-mediated immune toward tumor-associated including neoantigens. As a result, could not amplify any therapeutically...
ABSTRACT Extracellular vesicles (EVs) are small, heterogeneous and difficult to measure. Flow cytometry (FC) is a key technology for the measurement of individual particles, but its application analysis EVs other submicron particles has presented many challenges produced number controversial results, in part due limitations instrument detection, lack robust methods ambiguities how data should be interpreted. These complications exacerbated by field's reporting framework, EV‐FC manuscripts...
Extracellular vesicles (EV), including exosomes and microvesicles, are nano-sized intercellular communication vehicles that participate in a multitude of physiological processes. Due to their biological properties, they also promising candidates for the systemic delivery therapeutic compounds, such as cytokines, chemotherapeutic drugs, siRNAs viral vectors. However, low EV production yield rapid clearance administered by liver macrophages limit potential use vehicles. We have used...
Abstract Extracellular vesicles (EVs), including exosomes and microvesicles, are 30–800 nm that released by most cell types, as biological packages for intercellular communication. Their importance in cancer inflammation makes EVs their cargo promising biomarkers of disease cell-free therapeutic agents. Emerging high-resolution cytometric methods have created a pressing need efficient fluorescent labeling procedures to visualize detect EVs. Suitable labels must be bright enough one EV...
The tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived oxygenation as confirmed by positron emission tomographic (PET) imaging. CD8 CD4 tumor-infiltrating T lymphocytes (TIL) colon carcinomas, melanomas, breast adenocarcinomas are CD137 (4-1BB)-positive, opposed to their counterparts in tumor-draining lymph nodes spleen. Expression on activated markedly enhanced hypoxia the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Importantly, does...
Abstract Therapy for cancer can be achieved by artificially stimulating antitumor T and natural killer (NK) lymphocytes with agonist monoclonal antibodies (mAb). NK cells express several members of the TNF receptor (TNFR) family specialized in delivering a costimulatory signal on their surface. Engagement these receptors is typically associated proliferation, elevated effector functions, resistance to apoptosis, differentiation into memory cells. These lack any intrinsic enzymatic activity...
Abstract A current pressing need in cancer immunology is the development of preclinical model systems that are immunocompetent for study human tumors. Here, we report a humanized murine can be used to analyze pharmacodynamics and antitumor properties immunostimulatory monoclonal antibodies (mAb) settings where receptors targeted by mAbs expressed. Human lymphocytes transferred into immunodeficient mice underwent activation redistribution organs, they exhibited cell-surface expression hCD137...
The development of extracellular vesicles (EV) for therapeutic applications is contingent upon the establishment reproducible, scalable, and high-throughput methods production purification clinical grade EV. Methods including ultracentrifugation (U/C), ultrafiltration, immunoprecipitation, size-exclusion chromatography (SEC) have been employed to isolate EV, each facing limitations such as efficiency, particle purity, lengthy processing time, and/or sample volume. We developed a...
Abstract Agonist monoclonal antibodies (mAb) to the immune costimulatory molecule CD137, also known as 4-1BB, are presently in clinical trials for cancer treatment on basis of their effects primed T cells and perhaps other system. Here we provide evidence that CD137 is selectively expressed surface tumor endothelial cells. Hypoxia upregulated murine Treatment tumor-bearing immunocompromised Rag−/− mice with agonist mAb did not elicit any measurable antiangiogenic effects. In contrast,...
Significance Immunotherapy of cancer with immunomodulatory agents is achieving significant efficacy in an important fraction patients. The stimulatory inducible receptor T and NK lymphocytes known as CD137 or 4-1BB being stimulated agonist antibodies to enhance antitumor immunity clinical trials. In addition, the intracellular signaling domain crucial a component successful anti-leukemia therapies chimeric antigen receptors transduced into adoptively transferred lymphocytes. this study...
ABSTRACT Biological nanoparticles, including viruses and extracellular vesicles (EVs), are of interest to many fields medicine as biomarkers mediators or treatments for disease. However, exosomes small fall below the detection limits conventional flow cytometers due overlap particle‐associated scattered light signals with background instrument noise from diffusely light. To identify, sort, study distinct subsets EVs other individual particles, we developed nanoscale Fluorescence Analysis...
Immunostimulatory monoclonal antibodies (ISmAb) that unleash antitumor immune responses are showing efficacy in cancer clinical trials. Anti-B7-H1 (PD-L1) (mAb) block a critical inhibitory pathway T cells, whereas anti-CD137 and OX40 mAbs provide T-cell costimulation. A combination of these ISmAbs (anti-CD137 + anti-OX40 anti-B7-H1) was tested using transgenic mouse model multifocal rapidly progressing hepatocellular carcinoma, which c-myc drives transformation cytosolic ovalbumin (OVA) is...
While patients responding to checkpoint blockade often achieve remarkable clinical responses, there is still significant unmet need due resistant or refractory tumors. A combination of with further T-cell stimulation mediated by 4-1BB agonism may increase response rates and durability response. bispecific molecule that blocks the PD-1/PD-L1 axis localizes co-stimulation a PD-L1-positive tumor microenvironment (TME) draining lymph nodes could maximize antitumor immunity therapeutic window...
Abstract Agonist anti-CD137 (4-1BB) mAbs enhance CD8-mediated antitumor immunity. anti-human CD137 binding to four distinct epitopes on the glycoprotein costimulated T cell activation irrespective of engaged epitope or its interference with CD137L binding. perturbation all these agonist resulted in Ag and Ab internalization toward an endosomal vesicular compartment. Internalization was observed activated lymphocytes from humans mice, not only culture but also Ab-injected living animals....
Hypoxia is a common feature in solid tumors that has been implicated immune evasion. Previous studies from our group have shown hypoxia upregulates the co-stimulatory receptor CD137 on activated T lymphocytes and vascular endothelial cells. In this study, we show exposure of mouse human tumor cell lines to hypoxic conditions (1% O2) promotes transcription. However, resulting mRNA predominantly an alternatively spliced form encodes for soluble variant, lacking transmembrane domain....
Abstract Previous mouse and human studies have demonstrated that direct IFN-α/β signaling on naive CD8 T cells is critical to support their expansion acquisition of effector functions. In this study, we show primed in the presence IFN-α possess a heightened ability respond homeostatic cytokines secondary Ag stimulation, but rather than differentiating or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy adoptive immunotherapy....
Treatment with agonist anti-CD137 (4-1BB) immunostimulatory monoclonal antibodies elicits complete tumor regressions in a number of transplanted hematological and solid malignancies mice. Rejection is mainly dependent on cytotoxic T lymphocytes (CTL) IFNγ, although role for NK cells dendritic has been observed some models. EG7-derived thymomas shown to be CTL-dependent but not NK-dependent.In this therapeutic setting, we show that both the perforin-granzyme FasL effector systems are readily...
Dendritic cells (DC) are endowed with the ability to cross-present antigens from other cell types cognate T cells. DC poised meet polymorphonuclear leukocytes (PMNs) as a result of being co-attracted by interleukin-8 (IL-8), for instance produced tumor or infected tissue. Human monocyte-derived and mouse bone marrow-derived can readily internalize viable UV-irradiated PMNs. Such internalization was abrogated at 4°C partly inhibited anti-CD18 mAb. In mice, which had internalized PMNs...
Apolipoprotein A-I (Apo A-I) is a major component of high density lipoproteins (HDL) that transport cholesterol in circulation. We have constructed an expression plasmid encoding chimeric molecule encompassing interleukin-15 (IL-15) and Apo (pApo-hIL15) was tested by hydrodynamic injections into mice co-administered with the sushi domain IL-15Rα (pSushi) order to enhance IL-15 trans-presentation thereby bioactivity. The pharmacokinetics protein were much longer than non-stabilized its...
The benefits of anti-cancer agents extend beyond direct tumor killing. One aspect cell death is the potential to release antigens that initiate adaptive immune responses. Here, a diffusion enhanced formulation, INT230-6, containing potent cytotoxic agents, was administered intratumorally into large (approx. 300mm3) subcutaneous murine Colon26 tumors. Treatment resulted in regression from baseline 100% tumors and complete response up 90%. CD8+ or CD8+/CD4+ T double-depletion at treatment...
Abstract Anti‐CTLA‐4 monoclonal antibodies (mAb) that block the interaction of CTLA‐4 with CD80 and CD86 such as tremelimumab ipilimumab are currently being tested in clinic for cancer treatment exploiting their properties to de‐repress tumor‐specific cellular immunity. Addition fully human anti‐CTLA‐4 (tremelimumab) cultures T cells allogenic dendritic (DCs) did not increase proliferation. Magnetic bead‐mediated elimination CD4 + CD25 regulatory (T reg ) before setting up those alloreactive...