In vitro feasibility of next generation non-linear beamforming ultrasound methods to characterize and size kidney stones

BackgroundMesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein with high expression levels in an array of malignancies including mesothelioma, ovaria, non-small cell lung cancer, and pancreatic cancers and is an attractive target antigen for immune-based therapies. Early clinical evaluation of autologous MSLN-targeted chimeric antigen receptor (CAR)-T cell therapies for malignant pleural mesothelioma has shown promising acceptable safety1 and have recently evolved with incorporation of next-generation CAR co-stimulatory domains and armoring with intrinsic checkpoint inhibition via expression of a PD-1 dominant negative receptor (PD1DNR).2 Despite the promise that MSLN CAR-T therapies hold, manufacturing and commercial challenges using an autologous approach may prove difficult for widespread application. EBV T cells represent a unique, non-gene edited approach toward an off-the-shelf, allogeneic T cell platform. EBV-specific T cells are currently being evaluated in phase 3 trials [NCT03394365] and, to-date, have demonstrated a favorable safety profile including limited risks for GvHD and cytokine release syndrome.3 4 Clinical proof-of-principle studies for CAR transduced allogeneic EBV T cell therapies have also been associated with acceptable safety and durable response in association with CD19 targeting.5 Here we describe the first preclinical evaluation of ATA3271, a next-generation allogeneic CAR EBV T cell therapy targeting MSLN and incorporating PD1DNR, designed for the treatment of solid tumor indications.MethodsWe generated allogeneic MSLN CAR+ EBV T cells (ATA3271) using retroviral transduction of EBV T cells. ATA3271 includes a novel 1XX CAR signaling domain, previously associated with improved signaling and decreased CAR-mediated exhaustion. It is also armored with PD1DNR to provide intrinsic checkpoint blockade and is designed to retain functional persistence.ResultsIn this study, we characterized ATA3271 both in vitro and in vivo. ATA3271 show stable and proportional CAR and PD1DNR expression. Functional studies show potent antitumor activity of ATA3271 against MSLN-expressing cell lines, including PD-L1-high expressors. In an orthotopic mouse model of pleural mesothelioma, ATA3271 demonstrates potent antitumor activity and significant survival benefit (100% survival exceeding 50 days vs. 25 day median for control), without evident toxicities. ATA3271 maintains persistence and retains central memory phenotype in vivo through end-of-study. Additionally, ATA3271 retains endogenous EBV TCR function and reduced allotoxicity in the context of HLA mismatched targets. ConclusionsOverall, ATA3271 shows potent anti-tumor activity without evidence of allotoxicity, both in vitro and in vivo, suggesting that allogeneic MSLN-CAR-engineered EBV T cells are a promising approach for the treatment of MSLN-positive cancers and warrant further clinical investigation.ReferencesAdusumilli PS, Zauderer MG, Rusch VW, et al. Abstract CT036: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy. Cancer Research 2019;79:CT036-CT036.Kiesgen S, Linot C, Quach HT, et al. Abstract LB-378: Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial. Cancer Research 2020;80:LB-378-LB-378.Prockop S, Doubrovina E, Suser S, et al. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest 2020;130:733–747.Prockop S, Hiremath M, Ye W, et al. A Multicenter, Open Label, Phase 3 Study of Tabelecleucel for Solid Organ Transplant Subjects with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disease (EBV+PTLD) after Failure of Rituximab or Rituximab and Chemotherapy. Blood 2019; 134: 5326–5326.Curran KJ, Sauter CS, Kernan NA, et al. Durable remission following ‘Off-the-Shelf’ chimeric antigen receptor (CAR) T-Cells in patients with relapse/refractory (R/R) B-Cell malignancies. Biology of Blood and Marrow Transplantation 2020;26:S89.

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Next generation risk assessment (NGRA): Bridging in vitro points-of-departure to human safety assessment using physiologically-based kinetic (PBK) modelling – A case study of doxorubicin with dose metrics considerations

Toxicology in Vitro ◽

10.1016/j.tiv.2021.105171 ◽

2021 ◽

pp. 105171

Author(s):

Hequn Li ◽

Haitao Yuan ◽

Alistair Middleton ◽

Jin Li ◽

Beate Nicol ◽

...

Keyword(s):

Risk Assessment ◽

Safety Assessment ◽

Next Generation ◽

Human Safety ◽

Physiologically Based ◽

Dose Metrics

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In vitro imaging of kidney stones using ultra-short echo-time magnetic resonance

2015 IEEE 12th International Symposium on Biomedical Imaging (ISBI) ◽

10.1109/isbi.2015.7164153 ◽

2015 ◽

Author(s):

El-Sayed Ibrahim ◽

Robert Pooley ◽

Joseph Cernigliaro ◽

Mellena Bridges ◽

Jamie Giesbrandt ◽

...

Keyword(s):

Magnetic Resonance ◽

Kidney Stones ◽

Echo Time ◽

Short Echo Time

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Development of nanomedicines and nano-similars: recent advances in regulatory landscape

Current Pharmaceutical Design ◽

10.2174/1381612827666211115170001 ◽

2021 ◽

Vol 27 ◽

Author(s):

Rishi Paliwal ◽

Pramod Kumar ◽

Akash Chaurasiya ◽

Rameshroo Kenwat ◽

Sumeet Katke ◽

...

Keyword(s):

Drug Release ◽

Pharmaceutical Products ◽

Regulatory Agencies ◽

Next Generation ◽

Similar Drug ◽

Regulatory Guidelines ◽

The Moment ◽

Regulatory Landscape

Background: Nanopharmaceuticals serve as emerging forms of modern medicines which include nanomedicines, nanosimilars, nanotheranostics, nanodevices and many more. In last two decades, a large number of nano-based products has reached to the market and are being used clinically. Objectives: Unlike, conventional pharmaceutical products, nanopharmaceuticals behave differently both in vitro and in vivo and therefore, development of their generic versions needs special attention to replicate the similar drug release pattern leading to the identical therapeutic outcome. Further, drug-device combinations and 3D products are latest advancements in precise medicine delivery and development. Methods: The regulatory guidelines for these products are being framed at many stages by various regulatory agencies like USFDA/EMA and still are in infancy at the moment if we look at wider prospective and applications of nanomedicine. Results: For a formulation scientist, it is much needed that well-explained and directive guidelines should be available before leading to the development of the generic versions of these nano-cargos. Conclusion: Here, in this review, we have summarized the silent features of the regulatory perspectives related to the nanotechnology based next generation therapeutics and diagnostics.

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1348. In vitro Activity of Plazomicin, a Next-Generation Aminoglycoside, Against Carbapenemase-Producing Klebsiella pneumoniae

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1179 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S412-S413

Author(s):

Michael R Jacobs ◽

Caryn E Good ◽

Ayman M Abdelhamed ◽

Daniel D Rhoads ◽

Kristine M Hujer ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Carbapenem Resistance ◽

Vitro Activity ◽

In Vitro Activity ◽

Next Generation ◽

Aminoglycoside Resistance ◽

Carbapenem Resistant ◽

Carbapenemase Gene ◽

Research Grant

Abstract Background Plazomicin is a next-generation aminoglycoside with in vitro activity against multidrug-resistant Gram-negative species, including carbapenem-resistant isolates. The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) is a federally funded, prospective multicenter consortium of 20 hospitals from nine US healthcare systems to track carbapenem-resistant Enterobacteriaceae. Methods Minimum inhibitory concentrations (MICs) of plazomicin were determined by broth microdilution according to current CLSI guidelines against a collection of 697 carbapenem-resistant Klebsiella pneumoniae with defined carbapenem resistance mechanisms, including KPC and OXA carbapenemases. Isolates were submitted by participating CRACKLE centers. Results Carbapenemases present in study isolates included KPC-2 (n = 323), KPC-3 (n = 364), KPC-4 (n = 2), OXA-48 like (n = 7), and NDM (n = 1). Plazomicin MICs ranged from ≤0.12 to >32 mg/L, with MIC50 and MIC90 values of 0.25 and 1 mg/L, respectively (figure). MICs of 689 (98.8%) isolates were ≤4 mg/L, while MICs of the remaining eight isolates were >32 mg/L. Plazomicin MICs were related to specific carbapenemases present in isolates: of eight isolates with MICs >32 mg/L, seven contained OXA-48 like and one contained KPC-3, suggesting that these isolates possess an aminoglycoside-resistance mechanism on the same plasmid as their carbapenemase gene, such as a 16S ribosomal RNA methyltransferase, against which plazomicin is not active. Conclusion Plazomicin has good in vitro potency against a collection of carbapenemase-producing K. pneumoniae, with MIC90 value of 1 mg/L and MICs of ≤4 mg/L for 98.9% of isolates. Disclosures M. R. Jacobs, Achaogen: Investigator, Research grant. Shionogi: Investigator, Research grant. L. Connolly, Achaogen, Inc.: Consultant, Consulting fee. K. M. Krause, Achaogen: Employee, Salary. S. S. Richter, bioMerieux: Grant Investigator, Research grant. BD Diagnostics: Grant Investigator, Research grant. Roche: Grant Investigator, Research grant. Hologic: Grant Investigator, Research grant. Diasorin: Grant Investigator, Research grant. Accelerate: Grant Investigator, Research grant. Biofire: Grant Investigator, Research grant. D. Van Duin, achaogen: Scientific Advisor, Consulting fee. shionogi: Scientific Advisor, Consulting fee. Allergan: Scientific Advisor, Consulting fee. Astellas: Scientific Advisor, Consulting fee. Neumedicine: Scientific Advisor, Consulting fee. Roche: Scientific Advisor, Consulting fee. T2 Biosystems: Scientific Advisor, Consulting fee.

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In Vitro Evaluation of Bis-3-Chloropiperidines as RNA Modulators Targeting TAR and TAR-Protein Interaction

International Journal of Molecular Sciences ◽

10.3390/ijms23020582 ◽

2022 ◽

Vol 23 (2) ◽

pp. 582

Author(s):

Alice Sosic ◽

Giulia Olivato ◽

Caterina Carraro ◽

Richard Göttlich ◽

Dan Fabris ◽

...

Keyword(s):

Protein Interaction ◽

Chaperone Activity ◽

Next Generation ◽

In Vitro Evaluation ◽

Loop Domain ◽

Activation Response ◽

Analytical Approaches ◽

Bulge Loop ◽

Hiv 1

After a long limbo, RNA has gained its credibility as a druggable target, fully earning its deserved role in the next generation of pharmaceutical R&D. We have recently probed the trans-activation response (TAR) element, an RNA stem–bulge–loop domain of the HIV-1 genome with bis-3-chloropiperidines (B-CePs), and revealed the compounds unique behavior in stabilizing TAR structure, thus impairing in vitro the chaperone activity of the HIV-1 nucleocapsid (NC) protein. Seeking to elucidate the determinants of B-CePs inhibition, we have further characterized here their effects on the target TAR and its NC recognition, while developing quantitative analytical approaches for the study of multicomponent RNA-based interactions.

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