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18th ISAD

International Symposium on Albumin Dialysis

Cellular therapy as individual immune modulation and regeneration

The pathogenesis of liver failure in alcoholic hepatitis is complex and includes hepatic steatosis associated with inflammation, hepatocellular damage and rapid cholestasis. Increased translocation of the gut due to excessive alcohol is thought to exacerbate inflammation in acute events, creating a vicious cycle, where inflammation, cholestasis, toxin accumulation with consequent cellular damage perpetuate each other.

The concept of liver cell therapy in this condition is based on the assumption that by providing hepatocellular support, some of those spiraling down liver cell functions can be recovered, thereby breaking free of the vicious cycle enabling recovery. Out of the potential hepatocellular functions in question, we have identified the secretom of C3A cells u der static and dynamic conditions. Numerous proteins with immune modulatory and anti-inflammatory properties have been identified, the expression of which could be stimulated by various pro-inflammatory cytokines. One powerful anti-inflammatory protein, IL1-receptor antagonist, could not only be induced in vitro, but also rose significantly in vivo in subjects with acute alcoholic hepatitis randomly assigned to cell therapy compared to control subjects in the VTL 208 clinical trial.

Based on our current results, it appears, that C3A cell therapy could support the defective acute phase response at least in part. In addition, we identified several growth factors, such as TGF, VEGF etc. involved in the natural regeneration naturally following the acute phase response as the first line of response to injury. In order to identify the potential role of C3A cellular therapy to protect reserve hepatocellular capacity in the patient, we identified several anti-apoptotic and anti-oxidative mechanisms supported by C3A cells. For metabolic/detoxification support, we identified various p450 isoenzymes, which also reacted dynamically to challenges from patients plasma. Although we also could identify various bile acid and bilirubin transporters and metabolizing enzymes within C3A cells, the elimination of an excretory drain form the design of the delivery device does not explain the significant depletion of bilirubin seen in patients on extracorporeal therapy. It is hypothesized that metabolism into easier to excrete forms or recovery of patients own bile excretion due to anti-inflammatory, anti-apoptotic and anti-oxidative effects are responsible for the fact that significant more subjects on cellular therapy became Lille responders compared to control subjects in a controlled study in alcoholic hepatitis.

Last, not least, a considerable amount of proteins involved in the coagulation cascade have been identified from the C3A secretom. However, due to antagonizing adverse effects by extracorporeal circuits, studies so far have not shown improvements of global coagulation parameters. Detailed analysis, based on thromboelastography, are underway to further elucidate mechanisms of action for C3A cellular therapy to affect homeostasis. For further reference, please, refer to the attached listings of mechanism of action publications.

2014
Protein Content Assessment During Treatment with the ELAD® Bioartificial Liver Support System. Transplantation 2014; 98; 301-301

2014
ELAD® Bioartificial Liver Support System Overview and Measurement of Proteins During an Example Treatment. Rostock International Symposium on Albumin Dialysis (ISAD) meeting, 2014

2015
Expression of Liver-Specific Cytochrome P450 Isoenzymes and Oxygenases in C3A Cells Prior to and after Treatment with the ELAD® Liver Support System. Journal of Hepatology, 2015; 62: S263–S864.

2015
A randomized, open-label, multicenter, controlled study to assess safety and efficacy of ELAD® human cell-based bio-artificial liver support system (ELAD®) in subjects with alcohol-induced liver decompensation (AILD). Ashley, R.A. et al. Journal of Hepatology , Volume 62 , S844 - S845

2015
ELAD® VTL C3A Cells May Impact Liver Regeneration through Secreted Factors. Hepatology, 2015; 62(S1):1071A. 2015
Expression of Acute-Phase Proteins by ELAD® C3A Cells. Transplantation 2015; 99, Number 7S; 208-208

2015
The Effect of Extracorporeal C3a Cellular Therapy in Severe Alcoholic Hepatitis-The ELAD® Trial.” Hepatology, Volume 62, Number 6 (Suppl): 1379A

2015
Steroid Use Selects For A Less Sick Population With Improved Survival In A Clinical Trial Of The ELAD® System In Subjects With Alcoholic Hepatitis

2015
Case Study Of Inflammation Biomarkers in ELAD®-treated Alcohol-Induced Liver Decompensation Subjects Supports Adjusted Age, MELD and Creatinine Thresholds

2016
VTL C3A Cell Bile Acid Profile and Processing Capabilities,  Gastroenterology 150(4):S1122-S1123 · April 2016

2016
VTL C3A Cells Secrete Factors Involved in Coagulation Homeostasis.“ The FASEB Journal 30.1 Supplement (2016): 924-10.

2016
Phosphatidylethanol (PEth) in Blood as Marker of Alcohol Relapse (AR) in Subjects with Severe Alcoholic Hepatitis (sAH) in the ELAD® Phase 3 Clinical Trial. HEPATOLOGY, October, 2016; 142A

2016
Anti-Apoptotic Effects of Cellular Therapy: VTL C3A Cell-Secreted Factors Reduce in vitro Hepatocellular Injury via Multiple Mechanisms. 17th International Symposium on Albumin Dialysis (ISAD) 2016; September 16 - 18, 2016 in Rostock-Warnemünde, Germany.

2016
Hepatic Inflammation and Cellular Therapy. 17th International Symposium on Albumin Dialysis (ISAD) 2016; September 16 - 18, 2016 in Rostock-Warnemünde, Germany.

2016
Modeling of VTL C3A Cell-Secreted Protein Dosage During ELAD® Treatment for Acute Alcoholic Hepatitis. Tissue Engineering, 2016. Vol.22, Supplement 1, S1-S169.

2017
Early Change in Bilirubin Level (ECBL) as a Surrogate for Outcome in ELAD® Clinical Study of Severe Alcoholic Hepatitis (sAH)

2017
Lille score predicts outcome in an ELAD® clinical study of severe alcoholic hepatitis (sAH)

2017
Ethanol-Induced Oxidative Stress in Primary Human Hepatocytes is Suppressed by VTL C3A Cell-Secreted Factors 2017
Impact of the Systemic Inflammatory Response Syndrome on 3-month Mortality Rates in Subjects with Severe Alcoholic Hepatitis Treated with the ELAD® System

2017
Both MELD Score and Number of Organ Failures Defined by the Latest Chronic Liver Failure-Organ Failure Scoring System Effectively Select Subjects with Severe Alcoholic Hepatitis with Good Outcomes when Treated with the ELAD® System

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