Phase I/IIb trial: In-situ vaccine for metastatic colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS871-TPS871
Author(s):  
Madappa N. Kundranda ◽  
Tomislav Dragovich ◽  
Andrew Price ◽  
Philippe Lanauze ◽  
Miriam Bloch ◽  
...  
Keyword(s):  
Tumor Antigens ◽  
Intralesional Injection ◽  
Memory Cells ◽  
Serum Samples ◽  
Inflammatory Microenvironment ◽  
Immature Dendritic Cells ◽  
Optimal Dosing ◽  
Rejection Response ◽  
Bag Cells

TPS871 Background: Except for MSI-H tumors, CRC does not respond to immunotherapy. CRC does respond to the graft vs. tumor (GVT) immune effect that occurs after allogeneic stem cell transplantation. GVT is associated with GVHD toxicity which limits the clinical application. A bioengineered allograft (BAG) has been developed which can elicit host-mediated GVT-like effects without GVHD toxicity, chemotherapy conditioning or a HLA-matched donor. BAG are Th1 memory cells derived from blood of healthy donors with CD3/CD28 microbeads attached. These cells have immunomodulatory properties which enable modulation of Th1/Th2 balance and dysregulation of immunosuppressive circuits. We are evaluating the safety and efficacy of BAG in third-line mCRC. Methods: The study uses a standard 3+3 design followed by an expansion phase with the optimal dosing pattern. The protocol has four components: (A) priming; (B) in-situ vaccination; (C) extravasation and trafficking; and (D) counter immune suppression/avoidance. Priming involves intradermal injections of BAG cells which activates NK cells and develops allo-specific Th1/Tc1 immunity. In-Situ vaccination involves tumor cryoablation to release endogenous HSP which chaperone tumor neoantigens, followed immediately by the intralesional injection of BAG cells as adjuvant. Released HSP are engulfed and processed by immature dendritic cells (DC) attracted to the tissue damage. The inflammatory microenvironment created by the BAG and the subsequent allo-rejection response amplified by the priming induces DC maturation. These DC display processed tumor antigens on upregulated MHCI/II and express co-stimulatory CD80/86 enabling priming of a tumor-specific Th1/Tc1 response. CD40L and interferon-gamma expressed by BAG activates allo-specific and tumor-specific memory cells upon intravenous infusion, permitting trafficking to tumor. The host rejection of BAG releases endogenous danger signals creating a sustained systemic inflammatory cytokine release which serves to counter-regulate immunosuppressive mechanisms. Longitudinal CT scans biopsies, PBMC and serum samples are collected for analysis to verify immune events within each phase of the protocol. Clinical trial information: NCT02380443.

Enzyme-immobilized metal–organic framework nanosheets as tandem catalysts for the generation of nitric oxide

2018 ◽  
Vol 54 (79) ◽  
pp. 11176-11179 ◽  
Author(s):  
Pinghua Ling ◽  
Caihua Qian ◽  
Feng Gao ◽  
Jianping Lei
Keyword(s):  
Nitric Oxide ◽  
Metal Organic Framework ◽  
Serum Samples ◽  
Metal Organic ◽  
Organic Framework

An enzyme-immobilized metal–organic framework nanosystem was developed as a tandem catalyst for in situ generation of nitric oxide in serum samples.

scholarly journals A Simple, Rapid, Fluorometric Assay for Dopamine by In Situ Reaction of Boronic Acids and cis-Diol

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Xiaoxia Liu ◽  
Miaomiao Tian ◽  
Wenmei Gao ◽  
Jinzhong Zhao
Keyword(s):  
Low Cost ◽  
Boronic Acids ◽  
Emission Peak ◽  
Excitation Wavelength ◽  
Fluorescence Sensing ◽  
Serum Samples ◽  
Turn On ◽  
Rapid Reaction

An efficient, sensitive, and low-cost method has been developed for turn-on fluorescence sensing of dopamine (DA). The method relies on the rapid reaction of DA and 3-Hydroxyphenylboronic acid (3-HPBA) via specific recognition between boronic acids and cis-diol of DA in alkaline solution. The reaction product shows an excitation wavelength of 417 nm and the maximum emission peak at 470 nm. The proposed method allows the determination of DA in the range of 50 nM–25 μM, and the whole detection can be completed within 5 minutes. Furthermore, the presented approach has good selectivity and has been successfully applied to DA sensing in human serum samples, showing great potential in clinical diagnosis.

scholarly journals A platinum black-modified microelectrode for in situ olanzapine detection in microliter volumes of undiluted serum

2020 ◽  
Vol 127 (2) ◽  
pp. 291-299 ◽  
Author(s):  
Rajendra P. Shukla ◽  
Robert H. Belmaker ◽  
Yuly Bersudsky ◽  
Hadar Ben-Yoav
Keyword(s):  
Liquid Chromatography ◽  
Real Time ◽  
Psychotic Disorders ◽  
Limit Of Detection ◽  
Biological Fluids ◽  
In Situ Monitoring ◽  
Blood Levels ◽  
Platinum Black ◽  
Serum Samples

AbstractOlanzapine is a thienobenzodiazepine compound. It is one of the newer types of antipsychotic drugs used in the treatment of schizophrenia and other psychotic disorders. Several methods have been reported for analyzing olanzapine in its pure form or combined with other drugs and in biological fluids. These methods include high-performance liquid chromatography and liquid chromatography-tandem mass spectroscopy. Although many of the reported methods are accurate and sensitive, they require the use of sophisticated equipment, lack in situ analysis, and require expensive reagents. Moreover, several of these methods are cumbersome, require prolonged sample pretreatment, strict control of pH, and long reaction times. Here we present the development of a miniaturized electrochemical sensor that will enable minimally invasive, real-time, and in situ monitoring of olanzapine levels in microliter volumes of serum samples. For this purpose, we modified a microfabricated microelectrode with a platinum black film to increase the electrocatalytic activity of the microelectrode towards olanzapine oxidation; this improved the overall selectivity and sensitivity of the sensor. We observed in recorded voltammograms the anodic current dose response characteristics in microliter volumes of olanzapine-spiked serum samples that resulted in a limit of detection of 28.6 ± 1.3 nM and a sensitivity of 0.14 ± 0.02 µA/cm2 nM. Importantly, the platinum black-modified microelectrode exhibited a limit of detection that is below the clinical threshold (65–130 nM). Further miniaturizing and integrating such sensors into point-of-care devices provide real-time monitoring of olanzapine blood levels; this will enable treatment teams to receive feedback and administer adjustable olanzapine therapy.

scholarly journals Treatment of Metastatic Disease through Natural Killer Cell Modulation by Infected Cell Vaccines

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 434
Author(s):  
Seyedeh Raheleh Niavarani ◽  
Christine Lawson ◽  
Lee-Hwa Tai
Keyword(s):  
Infected Cell ◽  
Natural Killer ◽  
Tumor Antigens ◽  
Critical Role ◽  
Killer Cell ◽  
Oncolytic Viruses ◽  
Cell Vaccine ◽  
Tumor Killing

Oncolytic viruses (OVs) are a form of immunotherapy that release tumor antigens in the context of highly immunogenic viral signals following tumor-targeted infection and destruction. Emerging preclinical and clinical evidence suggests that this in situ vaccine effect is critical for successful viro-immunotherapy. In this review, we discuss the application of OV as an infected cell vaccine (ICV) as one method of enhancing the potency and breadth of anti-tumoral immunity. We focus on understanding and manipulating the critical role of natural killer (NK) cells and their interactions with other immune cells to promote a clinical outcome. With a synergistic tumor killing and immune activating mechanism, ICVs represent a valuable new addition to the cancer fighting toolbox with the potential to treat malignant disease.

In Situ Vaccination with TLR9 Agonist Combined with Local Radiation In Mycosis Fungoides: Analysis of Phase I/II Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 286-286 ◽  
Author(s):  
Youn H. Kim ◽  
Dita Gratzinger ◽  
Cameron Harrison ◽  
Joshua Brody ◽  
Debra Czerwinski ◽  
...  
Keyword(s):  
T Cells ◽  
Low Dose ◽  
Tumor Antigens ◽  
Vaccination Strategy ◽  
Large Cell ◽  
Low Dose Radiation ◽  
Clinical Responses ◽  
Local Radiation ◽  
Dose Radiation

Abstract Abstract 286 Background: In a murine model, our in situ vaccination therapy combining tumor antigens with TLR9 agonist cured mice of lymphoma. Our phase I/II study in indolent B-cell lymphoma demonstrated that this in situ vaccination maneuver utilizing local radiation to expose tumor antigens combined with CpG ODN was well-tolerated without treatment limiting toxicities. It induced meaningful systemic clinical responses and tumor-reactive memory CD8 T-cells. In parallel, we explored this in situ vaccination strategy in cutaneous T-cell lymphoma (CTCL), specifically mycosis fungoides (MF). Our objectives were to determine the feasibility and safety and to assess the local and systemic antitumor effects in MF. Methods: Patients with MF stages IA-IVA who failed ≥1 standard therapy were eligible. Immunization site was treated with low-dose radiation (2 Gy × 2 d), bracketed by intratumoral injection of CpG followed by weekly intratumoral CpG × 8. Local (immunized site) and systemic antitumor responses were assessed at wk 0, 2, 4, 8, 12, then monthly until PD/off-study. Clinical response was evaluated by assessing skin disease burden at sites not treated with immunization procedure. Results: Study enrollment was completed with total of 15 patients. Median age was 57 yrs (range 18–71 yrs), 12 of 15 were male. Six patients had stage IB and 9 with stage IIB (3 with large-cell transformation). Median number of prior therapies was 5 with range of 2–9. After the initial 6 patients, a second immunization site was added at wk 4 to enhance systemic response. Total of 5 partial responses were observed (30% OR); 2 of 6 treated with single immunization and 3 of 9 with dual immunization. Median time to response was 8 wks (range 4–12 wks), duration of response 7 wks (range 4–44 wks), and time to progression 20+ wks (range 3–44+ wks). Patients with large-cell transformed MF did not respond. Common toxicities were injection site and flu-like symptoms; mostly grade 1–2 and all transient. No clinical or laboratory findings of any autoimmune disorder were observed. Local tissue tumor/immune responses were assessed by immunostaining. CpG + local radiation treated immunization site showed a significant reduction of CD25+, Foxp3+ T-cells (p<0.01) consisting of MF cells and tumor-infiltrating lymphocytes. Similar reduction in S100+, CD1a+ dendritic cells (DCs) was observed post immunization (p < 0.025). A qualitative analysis suggested more remarkable reduction of CD25+ T-cells and skin DCs in clinical responders vs. non-responders (p= 0.058, 0.121). CpG dose-responsive activation of peripheral blood pDCs was observed in vitro. Conclusions: Our novel in situ vaccination strategy using a combination of intratumoral CpG ODN and low-dose radiation is feasible in CTCL/MF with acceptable toxicities. Depletion of tissue T-regs may be observed at immunized sites. Reduction of skin DCs may suggest cross-priming and migration of DCs to regional lymph nodes. Clinical responses in subset of patients and CpG responsiveness of pDCs may warrant further study with modifications to augment therapeutic effects. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pharmacokinetics of Intravenous Levofloxacin Administered at 750 Milligrams in Obese Adults

2011 ◽  
Vol 55 (7) ◽  
pp. 3240-3243 ◽  
Author(s):  
Aaron M. Cook ◽  
Craig Martin ◽  
Val R. Adams ◽  
R. Scott Morehead
Keyword(s):  
Standard Dose ◽  
Normal Weight ◽  
Serum Concentrations ◽  
Serum Samples ◽  
Obese Adults ◽  
Time Curve ◽  
Physiochemical Properties ◽  
Concentration Time ◽  
Optimal Dosing ◽  
Serial Serum

ABSTRACTThe physiochemical properties of levofloxacin suggest that it is an agent which may exhibit altered pharmacokinetics in obese individuals. The purpose of this study was to describe the pharmacokinetics of a single 750-mg intravenous dose of levofloxacin in both hospitalized and ambulatory obese individuals. The hypothesis was that a standard dose of levofloxacin in obese individuals would achieve serum concentrations likely to be therapeutic. A single levofloxacin dose of 750 mg was infused over 90 min, and seven serial serum samples were subsequently obtained to evaluate the pharmacokinetics after the first dose. The peak concentrations of levofloxacin were comparable to those seen with normal-weight individuals. However, the area under the concentration-time curve and clearance were quite variable. Accelerated clearance was evident in the ambulatory obese individuals. Further investigation of the effects of obesity on the pharmacokinetics of levofloxacin is necessary to ensure optimal dosing.

scholarly journals A Naturally Transmitted Epitheliotropic Polyomavirus Pathogenic in Immunodeficient Rats: Characterization, Transmission, and Preliminary Epidemiologic Studies

2017 ◽  
Vol 45 (5) ◽  
pp. 593-603 ◽  
Author(s):  
Cynthia Besch-Williford ◽  
Patricia Pesavento ◽  
Shari Hamilton ◽  
Beth Bauer ◽  
Beatrix Kapusinszky ◽  
...  
Keyword(s):  
Quantitative Polymerase Chain Reaction ◽  
Prostate Gland ◽  
Interleukin 2 ◽  
Epidemiologic Studies ◽  
Metagenomic Sequencing ◽  
Serum Samples ◽  
Diagnostic Assays ◽  
Wu Polyomavirus ◽  
Washington University

We report the identification, pathogenesis, and transmission of a novel polyomavirus in severe combined immunodeficient F344 rats with null Prkdc and interleukin 2 receptor gamma genes. Infected rats experienced weight loss, decreased fecundity, and mortality. Large basophilic intranuclear inclusions were observed in epithelium of the respiratory tract, salivary and lacrimal glands, uterus, and prostate gland. Unbiased viral metagenomic sequencing of lesioned tissues identified a novel polyomavirus, provisionally named Rattus norvegicus polyomavirus 2 (RatPyV2), which clustered with Washington University (WU) polyomavirus in the Wuki clade of the Betapolyomavirus genus. In situ hybridization analyses and quantitative polymerase chain reaction (PCR) results demonstrated viral nucleic acids in epithelium of respiratory, glandular, and reproductive tissues. Polyomaviral disease was reproduced in Foxn1rnu nude rats cohoused with infected rats or experimentally inoculated with virus. After development of RatPyV2-specific diagnostic assays, a survey of immune-competent rats from North American research institutions revealed detection of RatPyV2 in 7 of 1,000 fecal samples by PCR and anti-RatPyV2 antibodies in 480 of 1,500 serum samples. These findings suggest widespread infection in laboratory rat populations, which may have profound implications for established models of respiratory injury. Additionally, RatPyV2 infection studies may provide an important system to investigate the pathogenesis of WU polyomavirus diseases of man.

Prolonged release of VEGF and Ang1 from intralesionally implanted hydrogel promotes perilesional vascularization and functional recovery after experimental ischemic stroke

2022 ◽  
pp. 0271678X2110699
Author(s):  
Pavel Yanev ◽  
Geralda AF van Tilborg ◽  
Annette van der Toorn ◽  
Xiangmei Kong ◽  
Ann M Stowe ◽  
...  
Keyword(s):  
Functional Recovery ◽  
Release Kinetics ◽  
Chronic Phase ◽  
Stroke Recovery ◽  
Intralesional Injection ◽  
Prolonged Release ◽  
Post Stroke ◽  
In Situ Forming

Injectable hydrogels can generate and support pro-repair environments in injured tissue. Here we used a slow-releasing drug carrying in situ-forming hydrogel to promote post-stroke recovery in a rat model. Release kinetics were measured in vitro and in vivo with MRI, using gadolinium-labeled albumin (Galbumin), which demonstrated prolonged release over multiple weeks. Subsequently, this hydrogel was used for long-term delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) (Gel VEGF + Ang1, n = 14), in a photothrombotically induced cortical stroke lesion in rats. Control stroke animals were intralesionally injected with saline (Saline, n = 10), non-loaded gel (Gel, n = 10), or a single bolus of VEGF + Ang1 in saline (Saline VEGF + Ang1, n = 10). MRI was executed to guide hydrogel injection. Functional recovery was assessed with sensorimotor function tests, while tissue status and vascularization were monitored by serial in vivo MRI. Significant recovery from sensorimotor deficits from day 28 onwards was only measured in the Gel VEGF + Ang1 group. This was accompanied by significantly increased vascularization in the perilesional cortex. Histology confirmed (re)vascularization and neuronal sparing in perilesional areas. In conclusion, intralesional injection of in situ-forming hydrogel loaded with pro-angiogenic factors can support prolonged brain tissue regeneration and promote functional recovery in the chronic phase post-stroke.

Porcine circovirus type 2 and associated diseases in Romania — Short communication

2007 ◽  
Vol 55 (1) ◽  
pp. 151-156 ◽  
Author(s):  
D. Cadar ◽  
A. Cságola ◽  
Á. Dán ◽  
Z. Deim ◽  
Marina Spînu ◽  
...  
Keyword(s):  
Clinical Signs ◽  
Porcine Circovirus Type ◽  
Postweaning Multisystemic Wasting Syndrome ◽  
Porcine Circovirus Type 2 ◽  
Porcine Circovirus ◽  
Serum Samples ◽  
Associated Diseases ◽  
Wasting Syndrome

Porcine circovirus type 2 (PCV2) has been demonstrated to be the causal agent for postweaning multisystemic wasting syndrome (PMWS) and porcine dermatitis and nephropathy syndrome (PDNS). This report describes the first detection of PCV2 and associated diseases in a Romanian swine herd located in Transylvania. The clinical signs, pathological and histopathological changes observed in affected pigs were similar to those previously described for PDNS and PMWS. Polymerase chain reaction and in situ hybridisation were used for the detection of PCV2 nucleic acids from tissues and serum samples. Complete PCV2 genomes of both PMWS and PDNS cases were sequenced and analysed, and by comparing them with each other no genomic differences could be detected. The sequence analysis showed that the Romanian PCV2 was closely related to PCV2 identified in France and in Hungary.

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