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(申请人提供)：强化清髓细胞毒治疗后，自体造血干细胞移植(HSCT)在临床实践中经常被用来治愈或提高血液系统恶性肿瘤的存活率。III期随机试验表明，对于复发的大淋巴瘤患者，在巩固中高危和高危淋巴瘤的一线化疗以及治疗多发性骨髓瘤方面，该方法比非强化治疗更有效。在某些情况下，这种方法对缓解期的急性髓系白血病患者也可能是有益的。为了进行清髓性细胞毒化疗和/或放射治疗，HSCT总是需要重建造血活性。造血干细胞移植是一种复杂而昂贵的程序，涉及几个步骤，包括使用生长因子动员，多次白细胞分离(每次持续几个小时)以获得足够的造血干细胞(HSC)，在专门实验室处理和冷冻采集的细胞，并将细胞重新注入患者体内。此外，对于自体造血干细胞移植，人们总是担心移植可能会导致一些癌细胞回馈给患者。因此，在避免HSCT的同时进行强化治疗，对患者的造血功能恢复有很大的好处。我们的假设是，在强放疗或化疗之前或之后应用IL-12可能是一种简便、方便、安全和经济的方法，可以在不使用传统的HSCT的情况下诱导造血恢复。我们的进一步假设是，即使需要转移一些细胞，IL-12促进的造血恢复也可以显著减少HSC采集程序的数量，甚至与单独使用HSCT相比，甚至可能提供总体上改善的结果。我们基于广泛的初步数据，认为IL-12治疗与清髓治疗可以消除对HSCT的需求，或极大地减少骨髓消融后产生造血恢复所需的血细胞数量或类型，其中我们证明，单一、低剂量的IL-12可以在不使用任何移植细胞的情况下，在致命性照射的小鼠中再生近100%的造血活动和外周血细胞计数。为了产生体内的临床前数据并推进临床试验，我们建议在这些I期研究中将IL-12的使用与HSCT(健康骨髓细胞)的使用进行比较，以便直接评估它们各自在接受致命剂量辐射的小鼠中产生造血恢复的能力。如果拟议的实验证明IL-12可以消除或减少对HSCT的需求，我们建议继续进行STTR计划的第二阶段，以确定(在小鼠身上)开发一项临床试验的最佳条件，该临床试验将评估IL-12在接受有疗效意图的强化细胞毒治疗的恶性血液病患者中的使用，而不是传统的HSCT。