Abstract
We have developed a novel cell-based immunotherapy for treatment of some hematopoietic and blood deficient diseases such as aplastic anemia, chemotherapy-induced severe myelosuppression, idiopathic thrombocytopenia purpura and autoimmunity-induced cytopenia. Autologous and/or allogeneic peripheral blood mononuclear cells were cultured in vitro with a combination of cytokines and a calcium mobilizing agent for 2 days before given to patients via intravenous infusion. The immunotherapy has been shown to have potent activities in stimulating multi-lineage hematopoiesis and blood production including platelet production, which remains a major clinical problem to be solved. The immunotherapy is more effective for treatment of chronic and severe bone marrow failure and inefficient blood production than currently available growth factors of G-CSF, GM-CSF, Erythropoietin and IL-11. The mechanism of the immunotherapy is yet completely clear to us, however, some evidence suggests that in vitro activated immune cells produce and secrete multiple cytokines, working in concert, these cytokines released by the infused cells in organs important for hematopoiesis and blood production such as bone marrow, liver and spleen have remarkable effects on target cells, resulting in improved hematopoiesis, blood cell differentiation and maturation. In the preliminary clinical studies, more than 100 patients with aplastic anemia, severe chemotherapy-induced myelosuppression, systemic lupus erythematosus-associated cytopenia and idiopathic thrombocytopenia refractory to conventional therapies have been treated with the immunotherapy and the results have been encouraging. In severe idiopathic and benzene-induced aplastic anemia, 90% patients have complete or partial remission after the immunotherapy and one and half year survival is 90%. We have used 2–5x108in vitro activated allogeneic immune cells per infusion per day for 5 consecutive days, followed by small numbers of autologous infusions (1 to 10 million from approximately 50 ml of peripheral blood, depending on the severity of the disease, once a week for 4 weeks). This cycle of therapy is repeated till patient’s absolute neutrophil count is more than 0.5x109/L. The duration of the immunotherapy required for patients with AA to significantly improve ranges from two months to two years depending on the severity of the disease. Idiopathic thrombocytopenia is as difficult as aplastic anemia to treat for the immunotherapy and also requires relatively long time (several months to a year) for patients to respond to the therapy. Approximately 50% adult patients treated with the immunotherapy have complete or partial remission. In severe myelosuppression induced by chemotherapy in leukemia patients, the immunotherapy is highly effective and capable of reducing infection, bleeding and blood transfusion. The recovery of severe myelosuppression (from a few days to a month depending on the severity) after the immunotherapy is much quicker than that of aplastic anemia and idiopathic thrombocytopenia purpura. In conclusion, animal and preliminary human clinical studies suggest that the immunotherapy is highly effective for some bone marrow failure and blood deficient disorders, which are usually difficult to treat with the conventional therapies. The immunotherapy described here merits further investigation.
Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia