IL-12-Faciliated Hematopoietic Recovery Following Myeloablative Therapy

描述（由申请方提供）：在临床实践中，经常使用强化清髓性细胞毒性治疗后进行自体造血干细胞移植（HSCT），以治愈或改善血液恶性肿瘤的生存期。III期随机试验表明，这种方法在复发性大淋巴瘤患者中，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比非强化治疗更有效。在某些情况下，这种方法也可能对缓解期急性髓性白血病患者有益。为了给予清髓性细胞毒性化疗和/或放射治疗，总是需要HSCT来重建造血活性。HSCT是一种复杂且昂贵的程序，涉及几个步骤，包括用生长因子动员，多次白细胞去除术（每次持续几个小时）以获得足够的造血干细胞（HSC），在专门的实验室中处理和冷冻保存收获的细胞，并将细胞重新输注回患者体内。此外，对于自体HSCT，人们总是担心移植可能会导致一些癌细胞被送回患者体内。因此，如果能给予强化治疗，同时避免HSCT以恢复造血活性，对患者将是非常有益的。我们的假设是，在强化放疗或化疗之前或之后给予IL-12可能是一种简便、非常方便、安全且具有成本效益的诱导造血恢复的方法，而无需使用常规HSCT。我们进一步假设，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收集程序的数量，并且与单独的HSCT相比，甚至可以为患者提供总体改善的结果。IL-12治疗沿着清髓性治疗可以减少对HSCT的需要，或者大大减少骨髓清除后产生造血恢复所需的血细胞的数量或类型，这一观点是基于我们广泛的初步数据，其中我们证明了单一，低剂量的IL-12可以在不使用任何移植细胞的情况下使致死辐射小鼠的造血活性和外周血计数再生接近100%。为了产生体内临床前数据并向临床试验迈进，我们在这些I期研究中提出将IL-12给药与使用HSCT（健康骨髓细胞）进行比较，以便直接评估它们各自在接受致死剂量辐射的小鼠中产生造血恢复的能力。如果拟议的实验表明IL-12可以消除或减少对HSCT的需求，我们建议继续进行STTR项目的II期，以确定开发临床试验的最佳条件（小鼠），该临床试验将评估IL-12在接受强化细胞毒性治疗的血液恶性肿瘤患者中的使用，具有治愈目的，而不需要常规的HSCT。

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.