IL-12-Faciliated Hematopoietic Recovery Following Myeloablative Therapy

清髓治疗后 IL-12 促进造血恢复

• 批准号: 7218835
• 负责人: DAN DOUER
• 金额: $ 19.76万
• 依托单位: NEUMEDICINES, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218835
• 关键词: Acute Myelocytic Leukemia; Autologous; Back; Blood Cells; Blood Platelets; Blood typing procedure; Bone Marrow; Bone Marrow Aspiration; Bone Marrow Cell Transplantation; Bone Marrow Cells; Bone Marrow Purging; Bone Marrow Transplantation; CSF3 gene; Cancerous; Cell Count; Cell Transplants; Cell physiology; Cells; Clinical; Clinical Data; Clinical Trials; Collection; Complex; Condition; Count; Cytotoxic Chemotherapy; Data; Dose; Erythrocytes; Growth Factor; Harvest; Hematologic Neoplasms; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hour; Interleukin-11; Interleukin-12; Interleukin-3; Laboratories; Leukapheresis; Leukocytes; Lymphoma; Multiple Myeloma; Mus; Myeloid Leukemia in Remission; Natural regeneration; Numbers; Outcome; Pathology; Patients; Peripheral; Phase; Phase I Clinical Trials; Platelet Count measurement; Population; Procedures; Radiation; Radiation therapy; Randomized Controlled Clinical Trials; Rate; Recovery; Relapse; Risk; Small Business Technology Transfer Research; Stem cells; TimeLine; Transplantation; base; chemotherapy; cost; cytotoxic; improved; in vivo; neutrophil; peripheral blood; pre-clinical; programs; reconstitution; research study; stem

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：强化骨髓性细胞毒性治疗，然后是自体造血干细胞移植（HSCT），经常用于临床实践中，以治愈或改善血液学恶性肿瘤的存活率。 III期随机试验表明，这种方法比复发大淋巴瘤的患者更有效，在巩固前线化学疗法中，用于中等高风险和高风险淋巴瘤以及多发性骨髓瘤。在某些情况下，这种方法对缓解急性髓样白血病患者也可能是有益的。为了施用髓质性细胞毒性化学疗法和/或放射治疗，始终需要HSCT来重建造血活性。 HSCT是一个复杂且昂贵的程序，涉及多个步骤，包括与生长因子动员，多个持续数小时（每个小时持续几个小时）的动员，以获得足够的造血干细胞（HSC），加工和冷冻冷冻的专业实验室中收获的细胞，并将细胞重新置于患者中。此外，对于自体HSCT，始终担心移植可能导致一些癌细胞还给患者。因此，如果可以在避免HSCT恢复造血活性的同时进行强化疗法，这将对患者有很大的好处。我们的假设是，在不使用常规HSCT的情况下，强化放射或化学疗法之前或之后的给药可能是一种诱导造血恢复的一种简便，非常方便，安全和成本效益的方法。进一步的假设是，即使需要某些细胞的转移，IL-12-促进的造血恢复也可能会大大减少HSC收集程序的数量，甚至可能与HSCT相比，甚至可以为患者提供总体改善的结果。 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无需使用任何移植细胞的小鼠。为了产生体内临床前数据并向前迈进了临床试验，我们建议在这些阶段I研究中将IL-12给药与使用HSCT（健康骨髓细胞）的使用进行比较，以直接评估其各自在接受辐射剂量的小鼠中产生造血的能力。如果提出的实验表明IL-12可以消除或减少对HSCT的需求，我们建议继续进行STTR计划的II阶段，以确定最佳状况（在小鼠中）开发临床试验，以评估将在血液学恶性肿瘤中使用IL-12的患者使用IL-12的患者，这些患者接受强化的细胞毒性治疗，并接受了治愈性直觉的无关性HSSCT。