Project: Development of Tailored Leukapheresis treatment for patients with severe inflammatory complications of Sepsis.

Immune Therapy Holdings AB (ITH), Almac Group Ltd. (Almac) and Karolinska Institutet (KI) are forming a consortium to develop a novel Tailored Leukapheresis treatment (TLA) for the severe inflammatory complications of Sepsis. The project will include preclinical research, clinical trials and commercialization of a novel medical product through a commercial P within 33 months. _x000D__x000D_The proposed project is highly innovative, as the cellular apheresis achieved through TLA is essentially unexplored in sepsis. The project also addresses a serious clinical need, and can have high market potential in the USD 5 Billion a year (2010) sepsis treatment market (GlobalData, 2011). _x000D__x000D_ITH has previously collaborated with Almac and KI to develop the TLA platform for treatment of immune mediated inflammatory diseases (IMIDs). Through this process, ITH has successfully exploited the specificity in the homing of leukocytes to the gut in the development of a novel TLA column for the selective extracorporeal removal of circulating gut-homing leukocytes from IBD patients. ITH is currently evaluating the column treatment in a randomized placebo-controlled clinical trial, with promising preliminary data. The objective is to develop a TLA column for patients with severe inflammatory complications of sepsis. _x000D__x000D_Sepsis is a serious IMID condition characterized by a systemic inflammatory response due to an infectious agent. It has become more prevalent over the last decades, with an estimated incidence of over 600,000 cases/year in the United States (Martin, et al, 2000). It reCOs a highly lethal condition with a mortality of nearly 50% in a current international database (Martin, et al, 2009). In the septic patient, multiple organ failures such as acute respiratory distress syndrome (ARDS) often develop and require admission to an intensive care unit. _x000D__x000D_The complex pathophysiology of sepsis has gradually been elucidated over the last decade. Initially, a local infection induces the activation of tissue-resident immune cells, such as macrophages, which release proinflammatory cytokines. These substances, in turn, cause fever, vasodilatation and upregulation of adhesion molecules and chemokines on the surface of the vascular endothelia, enabling the recruitment of circulating immune cells. In peripheral blood, the neutrophilic granulocyte is the most abundant cell type and plays a pivotal role during the onset and propagation of the septic response. These cells are able to kill bacteria by phagocytosis and by release of highly toxic substances contained in their intracellular granulae. However, if the infection is not sufficiently controlled by these initial activities, propagation of the inflammatory response and continued influx of immune cells, now also including circulating monocytes and lymphocytes, inevitably results in tissue damage (Stearns-Kurosawa, 2011). _x000D__x000D_One of the most devastating complications of sepsis is ARDS, which is caused by pulmonary edema and extensive neutrophil accumulation in the alveoli, compromising gas exchange (Matthay & Zemans, 2011). Furthermore, systemic vasodilation and activation of the coagulation system cause hypotension and decreased tissue perfusion, ultimately resulting in organ dysfunction. Paradoxically, however, together with the intense immune activation, signs of immunosuppression, e.g., increased apoptosis of T and B lymphocytes, are present (Stearns-Kurosawa, et al, 2011). This complexity contributes to the difficulty in finding effective therapies in severe sepsis._x000D__x000D_The extravasation of immune cells is a multistep process, whereby the cell first migrates to the inflammatory site in response to a chemotactic gradient of chemokines and attaches to the vessel wall endothelium. The attached leukocyte is then subjected to attractants, chemokines, produced locally in the inflammatory tract, which upon binding to the matching chemokine receptor, induces transmigration and entry of the leukocyte effector cell into the inflamed tissue (von Andrian & Mackay, 2000). Importantly, specific chemokine – receptor pairs are differentially expressed in various tissues and on circulating subsets of immune cell (Agace, 2006 and Wurbel, et al, 2007)._x000D__x000D_This novel concept of TLA is based on the recognition that continued and exaggerated neutrophil recruitment underlies several of the pathophysiological aspects of severe sepsis, including organ damage, ARDS and release of proinflammatory mediators. It has been reported that chemokines, for example, CCR2 ligands, act as key players in inducing the neutrophil recruitment and correlate with the severity of patient illness in sepsis (Souto et al 2011). Furthermore, ITH has observed an intensive care patient with ARDS treated with unselective leukapheresis, using an ADA column, which eliminates neutrophils, monocytes and B cells. Upon treatment the patient’s condition improved dramatically, and she was taken off the respirator within 72 hours. _x000D_

Acronym	TLAS (Reference Number: 7121)
Duration	01/04/2012 - 31/12/2014
Project Topic	The consortium aims to develop a novel Tailored Leukapheresis column treatment for patients with severe inflammatory complications of sepsis. The project includes preclinical research, phase I/II clinical trials and concludes in the commercialization of the medical device.
Project Results (after finalisation)	We have identified an important cell population and a target chemokine receptor on neutrophils were we have developed and tested out the immobilization of chemokine in sepharosestreptavidine matrix.
Network	Eurostars
Call	Eurostars Cut-Off 7

Project partner

Number	Name	Role	Country
3	Almac Group Limited	Partner	United Kingdom
3	Immune Therapy Holdings	Coordinator	Sweden
3	Karolinska Institutet	Partner	Sweden