GRAFT-VERSUS-HOST-DISEASE


Transplantation of allogeneic (donor-derived) blood stem cells is a widely accepted medical procedure to restore normal blood cell production (hematopoiesis) in patients treated for blood or lymphatic cancers, or otherwise suffering from defective blood formation, or immunity. More and more patients receive such a transplant every year.

For successful transplantation, the blood stem cell graft must contain a minimum number of donor-derived T cells (immune cells). These can be beneficial in fighting any residual cancer cells - the graft versus leukemia effect. However, sometimes these donor-derived cells can attack the patient’s healthy tissue, causing graft-versus-host disease (GVHD). These immune processes are believed to be closely linked. Approximately 25% of blood stem cell transplant patients develop severe acute GVHD that does not respond adequately to standard first-line therapy. This number is expected to grow as the number of patients receiving high-risk transplants from unrelated donors increases.

Disease development
GVHD is thought to develop in several steps. Firstly, the chemotherapy or radiotherapy that destroys the patient’s own stem cells ahead of transplantation may create damage and inflammation to the patient’s gastrointestinal tract, liver and blood vessels, priming the environment and triggering donor-derived T cells to recognize their new host as ‘foreign’ and start an immune reaction. This reaction, in turn, activates additional players in the immune system, such as monocytes, macrophages and NK cells, resulting in further host tissue damage. Severe acute GVHD causes blistering of the skin, liver failure and severe diarrhea. It has a poor prognosis with five-year survival rates between 5 and 25%, depending on severity.

Current treatment options
Standard first-line therapy for acute GVHD consists of corticosteroids, which helps approximately 50% of patients. Once the disease progresses or if a disease is resistant to treatment, however, there are currently no approved therapies available, and so patients must rely on experimental (off-label) treatments, such as antibodies that cause depletion of T cells and/or other immune cells, or biologics and small molecule inhibitors that induce a functional suppression of the immune system. The often prolonged and rather broad immunosuppression induced by many of these agents frequently results in infectious complications and a potential loss of the graft-versus-leukemia effect, thereby nullifying the benefits achieved by controlling the GVHD reaction. The long-term survival of patients with steroid-resistant acute GVHD is only 20%; thus, there is an urgent need to develop more effective therapies to help more patients live longer, better lives.

T-Guard® as a promising investigational therapy
Xenikos has completed a Phase 1/2 study in 20 patients with severe steroid-refractory acute GVHD. Based on the results, the Company believes that T-Guard has the potential to offer a curative approach with a one-week treatment. Unlike other approaches, which only address symptoms, T-Guard is designed to actively restore immunological balance, providing a durable remedy for patients with this devastating and potentially fatal disease. Registration trials in the U.S. and EU are expected to start in 2019.

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