CytoSorb® Treatment of HLH - The Parallel to Cytokine Release Syndrome in Cancer Immunotherapy

MONMOUTH JUNCTION, N.J., March 20, 2017 /PRNewswire/ -- CytoSorbents Corporation (NASDAQ: CTSO), a critical care immunotherapy leader commercializing its flagship CytoSorb® blood filter to treat deadly inflammation in critically-ill and cardiac surgery patients around the world, highlights recent cases using CytoSorb to successfully treat HLH (hemophagocytic lymphohistiocytosis) and their relevance to cytokine release syndrome (CRS) in cancer immunotherapy.

Cancer immunotherapies manipulate a patient's own immune system to attack and kill cancer cells.  Examples of FDA-approved products or strategies under development include single and bispecific monoclonal antibodies, checkpoint inhibitors, therapeutic cancer vaccines, and adoptive T-cell transfer approaches using either chimeric antigen receptor T-cells (CAR T-cells) or T-cell receptor therapies.  Many of these therapies have led to immune system activation and a robust tumor response, resulting in impressive complete or partial response rates and disease-free survival, even in patients that had previously failed all other therapy. 

However, tight control of the immune response has been challenging, often resulting in immune system over-activation and excessive cytokine production called cytokine release syndrome, or CRS.  Reported in up to 50% of patients in some studies, this cytokine-mediated toxicity can range from mild, to severe and life-threatening.  Patients with severe CRS develop hallmark findings including high fever, high levels of cytokines, significantly elevated ferritin, coagulopathy and very low platelets, an enlarged liver and spleen, and ultimately some degree of multi-organ dysfunction and failure that can progress to death.  When treated quickly, patients may respond to anti-cytokine therapies such as the IL-6 receptor antagonist, tocilizumab, or to immunosuppressive agents such as high dose steroids.  However, these agents are not always effective, and steroids can compromise the viability or efficacy of the immunotherapy.

When CRS was first described, researchers noted the remarkable similarity to two related disorders called hemophagocytic lymphohistiocytosis (HLH) and macrophage activating syndrome (MAS).  In particular, the clinical, physical, laboratory, and inflammatory biomarker profiles in all three conditions overlap significantly.  In all of these diseases, many different types of white blood cells are activated, releasing inflammatory cytokines and creating a cytokine storm that then leads to rapid patient deterioration which is extremely difficult to manage. Between the familial HLH and secondary HLH triggered by infection (most commonly viral), the latter is more common, though both are relatively rare and often fatal, with steroids, immunosuppressive drugs, and anti-cytokine therapies often ineffective.

Despite the relative infrequency of HLH, we have now treated 10 secondary HLH patients with CytoSorb, with 3 published case reports and others pending. This month in the Journal of Clinical Immunology, in a case report entitled, "Rescue of Cytokine Storm Due to HLH by Hemoadsorption in a CTLA4-Deficient Patient", Greil and colleagues report the use of CytoSorb in successfully treating a 50-year old man with secondary HLH due to Epstein Barr virus (EBV) infection and associated Hodgkin's lymphoma, and complicated by CTLA-4 deficiency.  CTLA-4 deficiency is a genetic disorder that eliminates a key regulatory control element of cellular immunity and predisposes patients to severe inflammation.  This patient was initially admitted for recurrent fevers, and was subsequently found to have a high grade EBV infection that triggered HLH, with  kidney failure (requiring dialysis), liver failure, respiratory failure (requiring mechanical ventilation), shock (requiring vasopressors), and high inflammatory cytokines and other biomarkers.  Despite the use of conventional HLH therapy, including high dose steroids, etoposide, and rituximab due to EBV infection, the patient worsened with progressive multi-organ failure.  At that time, treatment with CytoSorb was initiated, subsequently treating for 4 consecutive days, each day with a new cartridge. According to the investigators, CytoSorb use resulted in an immediate decrease in inflammatory markers with a simultaneous immediate improvement in clinical condition, with the patient discharged from the ICU in stable condition, nine days after the start of CytoSorb therapy. 

This case follows other successful CytoSorb treatments in herpes simplex virus-induced HLH in a patient with fulminant liver failure, rapid clinical improvement in an HIV positive patient with EBV-induced HLH, and others pending submission or publication.  The success of CytoSorb treatment in a growing number of secondary HLH patients provides a clear rationale to treat CRS.  We have met with many immuno-oncology companies and have been invited to present to the immunotherapy sections and critical care units at several major cancer immunotherapy clinical trial sites.  In our discussions, we have confirmed the interest in the therapy, once available, as an adjunct to tocilizumab, and before high dose steroids are administered.  We plan to continue to pursue applications of our therapy in the treatment of CRS in the United States, Europe, and elsewhere, as cancer immunotherapies continue to expand worldwide.  CytoSorb is approved in the European Union, but is not yet approved in the United States.

About CytoSorbents Corporation (NASDAQ: CTSO)

CytoSorbents Corporation is a leader in critical care immunotherapy, specializing in blood purification. Its flagship product, CytoSorb® is approved in the European Union with distribution in 43 countries around the world, as a safe and effective extracorporeal cytokine adsorber, designed to reduce the "cytokine storm" or "cytokine release syndrome" that could otherwise cause massive inflammation, organ failure and death in common critical illnesses such as sepsis, burn injury, trauma, lung injury and pancreatitis, as well as in cancer immunotherapy. These are conditions where the risk of death is extremely high, yet no effective treatments exist. CytoSorb® is also being used during and after cardiac surgery to remove inflammatory mediators, such as cytokines and free hemoglobin, which can lead to post-operative complications, including multiple organ failure. CytoSorbents has completed its REFRESH (REduction in FREe Hemoglobin) 1 trial - a multi-center, randomized controlled study that has demonstrated the safety of intra-operative CytoSorb® use in a heart-lung machine during complex cardiac surgery.  In 2017, the company plans to initiate a pivotal REFRESH 2 trial intended to support U.S. FDA approval.  CytoSorb® has been used safely in more than 20,000 human treatments to date.  A companion product, VetResQ™, based on similar underlying technology to CytoSorb, is now commercially available in the United States for the treatment of hyper-inflammatory conditions in animal health.

CytoSorbents' purification technologies are based on biocompatible, highly porous polymer beads that can actively remove toxic substances from blood and other bodily fluids by pore capture and surface adsorption. Its technologies have received non-dilutive grant, contract, and other funding in excess of $18 million from DARPA, the U.S. Army, the U.S. Air Force, the U.S. Department of Health and Human Services, the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), U.S. Special Operations Command (SOCOM), and others. The Company has numerous products under development based upon this unique blood purification technology, protected by 31 issued U.S. patents and multiple applications pending, including CytoSorb-XL, HemoDefend™, ContrastSorb, DrugSorb, and others. For more information, please visit the Company's websites at www.cytosorbents.com and www.cytosorb.com or follow us on Facebook and Twitter.

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