Graft-versus-Host Disease

Leukemia and certain related conditions are often treated with radiation and chemotherapy to eliminate cancerous or diseased cells, but this process also severely compromises the native blood forming and immune system in the patient, leaving them susceptible to infection and other complications. To address this, a patient will often receive radiation and chemotherapy, followed by an allogeneic hematopoietic stem cell transplant (HSCT) or peripheral blood stem cell transplant.  Using these procedures, a patient's blood stem cells are replaced with a transplant of blood and immune forming stem cells, also referred to as hematopoietic stem cells, obtained from the bone marrow or peripheral blood of a healthy donor. Stem cell donors may be related or unrelated to the patient, but are matched according to tissue type in order to minimize the potential for graft-versus-host disease (GvHD), a common complication of such procedures where donor immune cells transplanted with the donor HSCT attack the tissue and organs of the patient. Following the transplant, the patient will often remain hospitalized in specialized units until successful engraftment provides a sufficiently functional immune system. 

According to the Center for International Blood and Marrow Transplant Research, there are approximately 25,000 allogeneic HSCTs performed annually globally, although this number is projected to increase due to the anticipated growth in incidence of hematologic malignancies associated with an aging population. While this treatment approach can be an effective medical therapy for these types of cancer, it is often associated with substantial tissue damage and side effects, such as GvHD.

GvHD is a frequent complication associated with allogeneic HSCT, affecting approximately half or more of transplant recipients, and advanced GvHD can be severely debilitating or even fatal. Several factors affect a patient's likelihood of having GvHD and GvHD severity, including the treatment protocol used, the degree of tissue match between donor and recipient (with lower GvHD rates and severity associated with related donors and better tissue matches), and the condition of the patient among other factors. In addition, higher GvHD rates are typically observed in patients receiving peripheral blood stem cell transplants, as compared to patients receiving bone marrow-derived stem cell transplants. Current treatment approaches involve the prophylactic use of agents such as methotrexate, cyclosporine, or tacrolimus, but these are also associated with various risks and side effects. Treatment of GvHD relies on the use of immunosuppressive agents such as corticosteroids (e.g., prednisone), but these may be transiently effective or ineffective in many patients, and even where effective, these treatments may have other side effects (e.g., infection, organ damage).


In preclinical studies, MultiStem has shown potent immunomodulatory properties, including the ability to reduce active inflammation through various modes of action, stimulate tissue repair and restore immune system balance. Accordingly, we believe that MultiStem could have broad application in the area of treating immune system disorders, including certain autoimmune diseases and other conditions.

An area of focus is the use of MultiStem as adjunctive treatment for HSC/bone marrow transplant used as therapy in hematologic malignancy. For many types of cancer, such as leukemia or other blood-borne cancers, treatment typically involves radiation therapy or chemotherapy, alone or in combination. Such treatment can substantially deplete the cells of the blood and immune system, by reducing the number of stem cells in the bone marrow from which they arise. The more intense the radiation treatment or chemotherapy, the more severe the resulting depletion is of the bone marrow, blood and immune system. Other tissues may also be affected, such as cells in the digestive tract and in the pulmonary system. The result may be severe anemia, immunodeficiency, substantial reduction in digestive capacity and other problems that may result in significant disability or death.

One strategy for treating the depletion of bone marrow is to perform a peripheral blood stem cell transplant or a bone marrow transplant. This approach may augment the patient’s ability to form new blood and immune cells and provide a significant survival advantage. However, finding a closely matched donor is frequently difficult or even impossible. Even when such a donor is found, in many cases there are immunological complications, such as GvHD, which may result in serious disability or death.

Working with leading experts in the stem cell and bone marrow transplantation field, we have studied MultiStem in animal models of radiation therapy and GvHD. In multiple animal models, MultiStem has been shown to be non-immunogenic, even when administered without the genetic matching that is typically required for conventional bone marrow or stem cell transplantation. Furthermore, in animal model systems testing immune reactivity of T-cells against unrelated donor tissue, MultiStem has been shown to suppress the T-cell-mediated immune responses that are an important factor in causing GvHD. MultiStem-treated animals also displayed a significant increase in survival relative to controls. As a result, we believe that the administration of MultiStem in conjunction with or following standard HSCT may have the potential to reduce the incidence or severity of complications and may enhance gastrointestinal function, which is frequently compromised as a result of radiation treatment or chemotherapy.

In 2010, we announced that we had been granted orphan drug designation by the FDA for MultiStem in the prevention of GvHD, which is intended to facilitate drug development, provides substantial potential benefits to the sponsor, including funding for certain clinical studies, study-design assistance, tax incentives and seven years of market exclusivity for the product upon regulatory approval. 

We completed a Phase I clinical trial examining the safety and tolerability of a single dose or repeat dosing of MultiStem administered intravenously to patients receiving a bone marrow or HSCT as part of their treatment of leukemia or other hematological condition. The trial was an open label, multicenter trial that involved leading experts in the field of bone marrow transplantation. In 2012, we announced the top-line results from the trial. We observed a consistent safety profile in both the single and multiple dose arms of the study, and at all dose levels tested. Although the trial was not specifically designed to demonstrate efficacy, we also observed clinically meaningful improvement in medically important parameters relative to historical clinical experience, including reduced incidence and severity of acute GvHD, improved relapse free survival, no graft failures, and enhanced engraftment rates relative to other forms of treatment. Data highlights from the study include:

  • All 36 patients experienced successful neutrophil engraftment (median time of engraftment 15 days), and 86% of patients experienced successful platelet engraftment (median time of engraftment 16 days) which compares favorably to historical clinical experience for this patient population demonstrating a positive impact on blood and immune system recovery;
  • Substantial reduction in acute GvHD incidence in those patients receiving a high single dose of MultiStem, relative to historical experience (11% grade II-IV GvHD, and 0% grade III-IV GvHD);
  • Evidence of a dose response relationship, with patients receiving the highest single dose of MultiStem having a 33% lower absolute incidence of acute GvHD relative to patients who received a single low or medium dose, and patients receiving once weekly dosing of the medium dose through the first 30 days having reduced GvHD incidence relative to single or weekly dosing over the first two weeks post-transplant;  
  • Limited infection-related complications over the first 100 days relative to historical clinical experience, consistent with the positive effect on engraftment rates; and
  • Favorable relapse-free survival (RFS) rate at 100 days among all patients receiving MultiStem treatment relative to the historical clinical experience.

We have engaged in a series of discussions with the FDA and other regulatory agencies to review the results from the Phase I trial and discuss plans for the next phase of clinical development, which could include a Phase 2/3 study of MultiStem for GvHD prophylaxis and HSCT support. We have submitted our proposed plan for such a study,and we have received initial feedback from the FDA and the EMA.