Intensive myeloablative cytotoxic treatment followed by autologous hematopoietic stem cell transplantation (HSCT) is frequently used in clinical practice to cure or improve survival of hematological malignancies. Phase III randomized trials have shown that this approach is more effective than non-intensive therapy in patients with relapsed large lymphoma, in consolidation of front line chemotherapy for intermediate-high and high risk lymphoma, and in treating multiple myeloma. In some instances, this approach also may be beneficial in patients with acute myeloid leukemia in remission. In order to administer myeloablative cytotoxic chemotherapy and/or radiation therapy, HSCT is always required to reconstitute hematopoietic activity. HSCT is a complex and expensive procedure involving several steps that include mobilization with growth factors, multiple sessions of leukapheresis (each lasting several hours) to obtain sufficient hematopoietic stem cells (HSC), processing and cryopreserving the harvested cells in a specialized laboratory and reinfusing the cells back into the patient. Additionally for an autologous HSCT, there is always a concern that the transplant might result in some cancerous cells being given back to the patient. Thus, it would be of great benefit to the patient if the intensive therapy could be given while avoiding HSCT for recovery of hematopoietic activity. It is our hypothesis that administration of IL-12 either before or after intensive radiation or chemotherapy could be a facile, very convenient, safe and cost-effective way to induce hematopoietic recovery without the use of a conventional HSCT. It is further our hypothesis that even if the transfer of some cells would be required, IL-12- facilitated hematopoietic recovery could significantly reduce the number of HSC collection procedures, and may even provide an overall improved outcome for patients as compared to HSCT alone. The notion that IL-12 therapy along with myeloablative therapy could either obviate the need for a HSCT, or greatly reduce the number or type of blood cells required to generate hematopoietic recovery following myeloablation, is based on our extensive preliminary data, where we demonstrate that a single, low dose of IL-12 can regenerate nearly 100% of hematopoietic activity and peripheral blood counts in lethally irradiated mice without the use of any transplanted cells. In order to generate in vivo pre-clinical data and move forward towards a clinical trial, we are proposing in these Phase I studies to compare IL-12 administration to the use of HSCT (healthy bone marrow cells) so as to directly assess their respective ability to generate hematopoietic recovery in mice which have received a lethal dose of radiation. If the proposed experiments demonstrate that IL-12 can eliminate or reduce the need for HSCT, we propose to continue to Phase II of the STTR program to determine the optimal conditions (in mice) for developing a clinical trial that would assess the use of IL-12 in patients with hematological malignancies who receive intensive cytotoxic therapy, with curative intent, without a conventional HSCT.
