DDRE-48. COMPARTMENT LOCKED IL-12 - INCREASED TISSUE RETENTION AND MINIMAL PERIPHERAL EXPOSURE ALLOW HIGHER TREATMENT EFFICACY AND TOLERABILITY IN LOCAL GLIOBLASTOMA THERAPY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi85-vi85
Author(s):  
Michal Beffinger ◽  
Linda Schellhammer ◽  
Tala Shekarian ◽  
Sereina Deplazes ◽  
Ivan Zimmermann ◽  
...  
Keyword(s):  
Treatment Efficacy ◽  
Therapeutic Potential ◽  
Systemic Exposure ◽  
Serum Levels ◽  
Full Potential ◽  
Convection Enhanced Delivery ◽  
Blood Concentrations ◽  
Binding Interface ◽  
Explant Cultures ◽  
Human Gbm

Abstract Recent clinical studies in glioblastoma (GBM) highlight the potential of local IL-12 therapy, but they also bring back tolerability concerns due to leakage into the periphery. This leakage might thus hamper exploiting the full potential of local IL-12 therapy. Fusion with an IgG4 Fc portion increases the tissue retention of IL-12; but could also confer export into the blood and subsequent systemic recycling through the neonatal Fc receptor (FcRn), ultimately leading to potentially toxic IL-12 serum levels. We assessed the expression of FcRn in human and murine GBM and its role in IL-12Fc tissue retention and systemic exposure upon local delivery. Human or murine IL-12Fc was injected in GBM-bearing or naïve wt or FcRn-humanized mice continuously or as bolus via convection-enhanced delivery (CED). We screened combinations of amino-acid substitutions at the (IL-12)Fc:FcRn binding interface to abolish this interaction. Brain and blood concentrations were assessed via ELISA or cytokine bead arrays. FcRn affinity was measured by SPR/ELISA and bioactivity tested on PBMCs and human GBM explant cultures. Treatment efficacy and immunological correlates were assessed in GBM bearing mice. FcRn is upregulated in human and mouse GBM and contributes to brain export and subsequent peripheral recycling of IL-12Fc in the blood. IL-12Fc with abrogated FcRn binding due to a unique set of substitutions is fully functional and appears brain compartment locked (CL IL-12) as it exhibits enhanced tissue retention and reduced serum levels upon local injection, reaching up 100x higher brain to serum concentration ratios than regular IL-12. Compared to its non-modified counterpart, murine CL IL-12 shows significantly higher treatment efficacy at negligible systemic footprint in late stage murine GBM. In patient explant cultures, human CL IL-12 leads to successful inflammatory conditioning. Compartment locked IL-12 should thus allow a wide dosing window to fully harness its therapeutic potential for local GBM therapy.

scholarly journals Convection-Enhanced Delivery for Targeted Delivery of Antiglioma Agents: The Translational Experience

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Jonathan Yun ◽  
Robert J. Rothrock ◽  
Peter Canoll ◽  
Jeffrey N. Bruce
Keyword(s):  
Side Effects ◽  
Targeted Delivery ◽  
Systemic Exposure ◽  
Systemic Delivery ◽  
Convection Enhanced Delivery ◽  
Widespread Application ◽  
Wide Range ◽  
Systemic Side Effects ◽  
Human Gbm ◽  
The Ideal

Recent improvements in the understanding of glioblastoma (GBM) have allowed for increased ability to develop specific, targeted therapies. In parallel, however, there is a need for effective methods of delivery to circumvent the therapeutic obstacles presented by the blood-brain barrier and systemic side effects. The ideal delivery system should allow for adequate targeting of the tumor while minimizing systemic exposure, applicability across a wide range of potential therapies, and have existing safe and efficacious systems that allow for widespread application. Though many alternatives to systemic delivery have been developed, this paper will focus on our experience with convection-enhanced delivery (CED) and our focus on translating this technology from pre-clinical studies to the treatment of human GBM.

scholarly journals SCIDOT-06. TOWARDS EXCLUSIVELY LOCAL THERAPY OF GLIOBLASTOMA - ENGINEERING IL-12Fc WITH SUPERIOR TISSUE RETENTION AND MINIMAL SYSTEMIC EXPOSURE AFTER CNS ADMINISTRATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi273-vi273
Author(s):  
Michal Beffinger ◽  
Linda Schellhammer ◽  
Stanislav Pantelyushin ◽  
Iwan Zimmermann ◽  
Pascal Egloff ◽  
...  
Keyword(s):  
Local Treatment ◽  
Systemic Exposure ◽  
Local Therapy ◽  
Serum Levels ◽  
Therapeutic Window ◽  
Convection Enhanced Delivery ◽  
Interaction Interface ◽  
Heavy Chain Constant Region ◽  
The Impact

Abstract Intratumoral application of IL-12 overrides the prevailing glioblastoma (GB) associated immunosuppression and can trigger efficient anti-tumor responses. With clinical studies currently testing local expression of IL-12 in brain tumors, concerns on IL-12 systemic toxicity via leakage resurface. The fusion to an immunoglobulin heavy chain constant region (“Fc tag”) should increase tissue retention of IL-12. However, export of IL-12Fc into the blood via the neonatal Fc receptor (FcRn) could nevertheless lead to systemic exposure. Subsequent systemic recycling via FcRn could lead to gradually increasing and eventually toxic serum concentrations. We analysed the effect of the Fc-tag on IL-12 tissue retention and evaluated whether FcRn also is involved in brain export and systemic recycling of IL-12Fc upon local delivery. Human or murine IL-12Fc was delivered in GB-bearing or naïve wt or FcRn-humanized mice (mFcRn-/- hFcRn tg) continuously via mini osmotic pumps or as bolus via convection-enhanced delivery (CED). Brain and blood concentration levels were assessed via ELISA. FcRn affinity of IL-12Fc mutants was assessed via ELISA and surface plasmon resonance. We observed much higher tissue retention of IL-12Fc compared to unmodified IL-12, but also an FcRn-dependent gradual increase of IL-12Fc serum levels. Testing a battery of amino acid substitutions at the FcRn interaction interface, we discovered unique substitutions that largely abolish brain export and systemic accumulation while preserving IL-12Fc functionality, leading to an over 100-fold higher brain to blood ratio than unmodified IL-12. We currently test the impact on efficacy of local IL-12Fc and checkpoint brain tumor treatment in vivo. Achieving high local concentrations at low to absent systemic exposure is an important prerequisite for a large therapeutic window for local treatment of neurologic diseases. The novel Fc-modifications present a promising platform for reducing systemic leakage of Fc-containing therapeutics in the context of continuous or intermittent CNS delivery beyond brain cancer therapy.

Integrating Bioinformatics Strategies in Cancer Immunotherapy: Current and Future Perspectives

2020 ◽  
Vol 23 (8) ◽  
pp. 687-698 ◽  
Author(s):  
Houda N. Washah ◽  
Elliasu Y. Salifu ◽  
Opeyemi Soremekun ◽  
Ahmed A. Elrashedy ◽  
Geraldene Munsamy ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Therapeutic Potential ◽  
Cell Cancer ◽  
Full Potential ◽  
Future Perspectives ◽  
The Past ◽  
Bioinformatics Tools ◽  
Treatment Paradigm ◽  
Immunotherapy Of Cancer ◽  
Significant Attention

For the past few decades, the mechanisms of immune responses to cancer have been exploited extensively and significant attention has been given into utilizing the therapeutic potential of the immune system. Cancer immunotherapy has been established as a promising innovative treatment for many forms of cancer. Immunotherapy has gained its prominence through various strategies, including cancer vaccines, monoclonal antibodies (mAbs), adoptive T cell cancer therapy, and immune checkpoint therapy. However, the full potential of cancer immunotherapy is yet to be attained. Recent studies have identified the use of bioinformatics tools as a viable option to help transform the treatment paradigm of several tumors by providing a therapeutically efficient method of cataloging, predicting and selecting immunotherapeutic targets, which are known bottlenecks in the application of immunotherapy. Herein, we gave an insightful overview of the types of immunotherapy techniques used currently, their mechanisms of action, and discussed some bioinformatics tools and databases applied in the immunotherapy of cancer. This review also provides some future perspectives in the use of bioinformatics tools for immunotherapy.

scholarly journals Analysis of serum levels of titanium and aluminium ions in patients with early onset scoliosis operated upon using the magnetic growing rod—a single centre study of 14 patients

2021 ◽  
Author(s):  
Mandar Deepak Borde ◽  
Sarang Sapare ◽  
Emile Schutgens ◽  
Chadi Ali ◽  
Hilali Noordeen
Keyword(s):  
Early Onset ◽  
Serum Levels ◽  
Early Onset Scoliosis ◽  
Ion Concentration ◽  
Long Term Effects ◽  
Blood Concentrations ◽  
Growing Rod ◽  
Rod System ◽  
Rod Breakage

Abstract Study design A cross-sectional retrospective Level 3 study. Objective To study the serum levels of Titanium and Aluminium ions in patients operated using the magnetically controlled growing rod (MCGR) system. Summary of background data 14 consecutive patients of early onset scoliosis with varying etiology managed with MCGR system with a minimum follow-up of 24 months were selected for the study. The group consisted of two boys (14.3%) and 12 girls (85.7%). The average age of the patients at the time of surgery was 10.4 years (5–15 years). The average period of follow-up was 43.7 months (28–79 months). After informed consent of the subjects and their caretakers, serum levels of titanium and aluminium were measured. These levels were then assessed with regards to the number of screws used, number of distractions and complications. Methods The concentration of titanium and aluminium ions in the serum was measured using high resolution inductively coupled plasma mass spectrometry. Results For the sake of ease of assessment, patients were divided into three etiology-based groups—idiopathic (n = 6), neuromuscular (n = 2) and syndromic (n = 6). The mean serum titanium level was 15.9 μg/L (5.1–28.2 μg/L) while that of aluminium was 0.1 μmol/L (0.1–0.2 μmol/L). Of the 14 patients, 2 (14.2%) patients had mechanical failure (actuator pin dysfunction), 3 (21.4%) had rod breakage requiring revision surgery and one patient (7.1%) had surgical site infection managed with appropriate antibiotics. Patients undergoing revision for rod breakage did not show any metallosis of the tissues during surgery. Conclusion Analysis of patients with scoliosis operated using the magnetic growing rod system concludes that it is accompanied by presence of titanium in the blood but whether clinically significant or not needs to be ascertained by comparison of preoperative and postoperative blood concentrations of the titanium ions in individual subjects. The aluminium ion concentration remains within normal limits. Though implant malfunction may raise the titanium levels in the blood, its clinical significance needs to be determined. The aluminium levels are not affected irrespective to the presence or absence of complications. The long-term effects of raised titanium levels in the blood also warrant further prospective studies designed for precise and deeper analyses.

scholarly journals In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 615
Author(s):  
Shang-En Huang ◽  
Erna Sulistyowati ◽  
Yu-Ying Chao ◽  
Bin-Nan Wu ◽  
Zen-Kong Dai ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Serum Levels ◽  
Gene Expressions ◽  
Tnf Α ◽  
Anti Inflammatory

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

scholarly journals Convection Enhanced Delivery in the Setting of High-Grade Gliomas

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 561
Author(s):  
Chibueze D. Nwagwu ◽  
Amanda V. Immidisetti ◽  
Michael Y. Jiang ◽  
Oluwasegun Adeagbo ◽  
David C. Adamson ◽  
...  
Keyword(s):  
Rapid Development ◽  
Systemic Exposure ◽  
Therapeutic Index ◽  
High Grade Glioma ◽  
High Grade ◽  
Clinical Experiences ◽  
Convection Enhanced Delivery ◽  
Drug Concentrations ◽  
Infiltrative Growth Pattern ◽  
High Grade Gliomas

Development of effective treatments for high-grade glioma (HGG) is hampered by (1) the blood–brain barrier (BBB), (2) an infiltrative growth pattern, (3) rapid development of therapeutic resistance, and, in many cases, (4) dose-limiting toxicity due to systemic exposure. Convection-enhanced delivery (CED) has the potential to significantly limit systemic toxicity and increase therapeutic index by directly delivering homogenous drug concentrations to the site of disease. In this review, we present clinical experiences and preclinical developments of CED in the setting of high-grade gliomas.

MAPK/AP-1-Targeted Anti-Inflammatory Activities of Xanthium strumarium

2016 ◽  
Vol 44 (06) ◽  
pp. 1111-1125 ◽  
Author(s):  
Muhammad Jahangir Hossen ◽  
Mi-Yeon Kim ◽  
Jae Youl Cho
Keyword(s):  
Mouse Model ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Elevated Serum ◽  
Human Monocyte ◽  
Serum Levels ◽  
Mitogen Activated Protein Kinase ◽  
Xanthium Strumarium ◽  
U937 Cells ◽  
Anti Inflammatory

Xanthium strumarium L. (Asteraceae), a traditional Chinese medicine, is prescribed to treat arthritis, bronchitis, and rhinitis. Although the plant has been used for many years, the mechanism by which it ameliorates various inflammatory diseases is not yet fully understood. To explore the anti-inflammatory mechanism of methanol extracts of X. strumarium (Xs-ME) and its therapeutic potential, we used lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 cells and human monocyte-like U937 cells as well as a LPS/D-galactosamine (GalN)-induced acute hepatitis mouse model. To find the target inflammatory pathway, we used holistic immunoblotting analysis, reporter gene assays, and mRNA analysis. Xs-ME significantly suppressed the up-regulation of both the activator protein (AP)-1-mediated luciferase activity and the production of LPS-induced proinflammatory cytokines, including interleukin (IL)-1[Formula: see text], IL-6, and tumor necrosis factor (TNF)-[Formula: see text]. Moreover, Xs-ME strongly inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) in LPS-stimulated RAW264.7 and U937 cells. Additionally, these results highlighted the hepatoprotective and curative effects of Xs-ME in a mouse model of LPS/D-GalN-induced acute liver injury, as assessed by elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and histological damage. Therefore, our results strongly suggest that the ethnopharmacological roles of Xs-ME in hepatitis and other inflammatory diseases might result from its inhibitory activities on the inflammatory signaling of MAPK and AP-1.

Computational Model of Interstitial Transport in the Rat Brain Using Diffusion Tensor Imaging

2007 ◽  
Author(s):  
Jung Hwan Kim ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont
Keyword(s):  
Diffusion Tensor ◽  
Therapeutic Potential ◽  
Treatment Optimization ◽  
Convection Enhanced Delivery ◽  
Tissue Properties ◽  
Large Molecules ◽  
Macromolecular Drugs ◽  
Interstitial Transport ◽  
Blood Spinal Cord Barrier ◽  
The Brain

In spite of the high therapeutic potential of macromolecular drugs, it has proven difficult to apply them to recovery after injury and treatment of cancer, Parkinson’s disease, and other neurodegenerative diseases. One barrier to systemic administration is low capillary permeability, i.e., the blood-brain and blood-spinal cord barrier. To overcome this barrier, convection-enhanced delivery (CED) infuses agents directly into tissue to supplement diffusion and increase the distribution of large molecules in the brain [1,2]. Predictive models of distribution during CED would be useful in treatment optimization and planning. To account for large infusion volumes, such models should incorporate tissue boundaries and anisotropic tissue properties.

scholarly journals Towards Better Delivery of Cannabidiol (CBD)

2020 ◽  
Vol 13 (9) ◽  
pp. 219 ◽  
Author(s):  
Sophie Anne Millar ◽  
Ryan Francis Maguire ◽  
Andrew Stephen Yates ◽  
Saoirse Elizabeth O’Sullivan
Keyword(s):  
Solid State ◽  
Drug Delivery Systems ◽  
Therapeutic Agent ◽  
Water Solubility ◽  
Therapeutic Potential ◽  
Development Programme ◽  
Full Potential ◽  
Pharmaceutical Development ◽  
Pharmacokinetic Profiles ◽  
Full Development

Cannabidiol (CBD) has substantial therapeutic potential, but its development as an effective drug by the pharmaceutical industry is hindered by intrinsic characteristics such as low bioavailability, low water solubility, and variable pharmacokinetic profiles. Importantly, lack of patentability of the drug substance also limits the likelihood of an expensive, full development programme in anything other than orphan indications. Potential avenues to overcome these issues with CBD include self-emulsifying drug delivery systems, improved crystal formulations and other solid-state delivery formulations, which are mostly in the pre-clinical or early clinical stages of development. This review identifies issues compromising current delivery of solid-state CBD, and how advanced pharmaceutical development strategies can enable CBD to realise the full potential as a successful therapeutic agent.

Serum Levels of Melatonin in Cancer Patients and their Relation to Body Sizes

1988 ◽  
Vol 3 (3) ◽  
pp. 193-196 ◽  
Author(s):  
S. Barni ◽  
P. Lissoni ◽  
S. Crispino ◽  
F. Rovelli ◽  
G. Esposti ◽  
...  
Keyword(s):  
Body Weight ◽  
Body Size ◽  
Cancer Patients ◽  
Serum Levels ◽  
Blood Levels ◽  
Melatonin Secretion ◽  
Normal Range ◽  
Blood Concentrations ◽  
Patients With Cancer ◽  
Body Sizes

Melatonin secretion is often enhanced in patients with cancer. In the light of a reported correlation between melatonin levels and body size, we investigated blood levels of this pineal hormone in a group of 72 patients affected by cancer, 30 of whom had body weight within the normal range, 30 were obese and the last 12 cases had body weight below the normal range, in order to establish whether in fact melatonin blood concentrations were related to body size. Melatonin levels were high in 19/72 patients (26%). The mean levels of the pineal hormone were similar in patients with normal, low and high body weight. Finally, there was no significant correlation between melatonin values and body weight, height or surface. Melatonin secretion thus does not appear to be influenced by body size in cancer patients.

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