IL-15 Superagonist Complex as an Immunotherapeutic for Multiple Myeloma

IL-15 超级激动剂复合物作为多发性骨髓瘤的免疫治疗药物

基本信息

批准号：
8714705
负责人：
HING C. WONG
金额：
$ 75万
依托单位：
ALTOR BIOSCIENCE. LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-11 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714705
关键词：
Age American Animal Model Animals Antitumor Response Apoptosis Apoptotic Autologous Stem Cell Transplantation Biological Bone Diseases Bone Marrow Bone Marrow Cells Bortezomib CD8B1 gene Cell Adhesion Molecules Cell secretion Cells Cessation of life Chimeric Proteins Clinical Clinical Trials Comorbidity Complement Complex Cyclic GMP Development Diagnosis Disease Dose Drug Kinetics Effectiveness Elderly Evaluation Exhibits Functional disorder Funding Mechanisms Goals Growth Growth Factor Hematologic Neoplasms High Dose Chemotherapy Hypercalcemia IgG1 Immune Immune response Immunity Immunocompetent Immunotherapeutic agent Immunotherapy Interferons Interleukin-15 Interleukin-2 Kidney Failure Laboratory Animal Models Life Life Expectancy Malignant Neoplasms Memory Metastatic Melanoma Modality Multiple Myeloma Mus Natural Killer Cells Newly Diagnosed Paraproteinemias Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Plasma Cells Play Population Production Property Proteasome Inhibitor Recording of previous events Recurrent disease Refractory Refractory Disease Relapse Residual Neoplasm Resistance Role Safety Small Business Innovation Research Grant Staging Survival Rate T memory cell T-Lymphocyte Thalidomide Therapeutic Time Toxicology Treatment Protocols United States base cell growth cell killing cell mediated immune response chemotherapy cytokine improved interleukin-15 receptor lenalidomide mutant neoplastic cell next generation novel preclinical study protein complex public health relevance receptor research clinical testing response standard of care success tumor

项目摘要

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy with an estimated 22,350 newly diagnosed cases and 10,710 deaths due to MM in the United States in 2013. MM, typically a disease of the elderly, is a malignancy of clonal plasma cells in the bone marrow (BM) characterized by the presence of paraproteinemia, destructive bone disease, hypercalcemia, renal failure, and/or hematological dysfunction. Although survival rates of MM patients have improved by recent therapeutic advances, MM remains incurable due to the persistence of minimal residual disease. Hence, novel modalities complementing or improving current treatment options are desperately needed. There is ample evidence that immunomodulatory drugs are effective against MM. Thus, the use of a potent immunotherapeutic is an attractive approach to provide durable immune responses to or even potentially cure patients with MM. Interleukin-15 (IL-15), a crucial factor for the development, proliferation and activation of effector NK cells and CD8+ memory T cells, exhibits potent anti-tumor activities against well-established tumors in animal models. Based on its properties, IL-15 is considered by NCI as the most promising immunotherapeutic product candidate that could potentially cure cancer. We have previously isolated a novel proprietary IL-15 mutant with increased biological activity. The immunostimulatory properties of this superagonist IL-15 (IL-15N72D) was further improved by creating a complex with an IL-15 receptor ¿ - IgG1 fusion protein. We postulate that administration of this complex (referred to as ALT-803) will induce a durable, potent and broad cell-mediated immune response, which could result in efficacious and potentially curative effects in patients with MM. This approach is supported by results of our SBIR Phase I project indicating that ALT-803 indeed eradicated well- established myeloma tumors and prolonged survival of tumor-bearing mice through a novel mechanism dependent on the activation of CD8+ memory T cells and secretion of IFN-y from these T cells. Furthermore, short-term ALT-803 treatment provided long-lasting T cell dependent immunological effects that completely protected mice against subsequent tumor cell rechallenge. These studies provide a strong rationale for advancing ALT-803 into clinical testing against MM as a curative treatment. In addition to the SBIR Phase I project, we have completed animal toxicology studies and manufacture of ALT-803 clinical product allowing FDA acceptance of an IND for clinical use of ALT-803 in other cancer indications. Under this SBIR Phase II proposal, we plan to conduct a multicenter Phase 1/2 study to investigate the safety, pharmacokinetics, and immunostimulatory and clinical activities of ALT-803 in patients with refractory or relapsed MM. Successful completion of this study will pave the way for further evaluation of ALT-803 either as monotherapy or in combination with chemotherapies in patients with relapsed/refractory MM with the ultimate goal of developing more durable or curative therapeutic options for treatment-na¿ve and/or relapsed/refractory MM patients.

描述（由适用提供）：多发性骨髓瘤（MM）是第二常见的血液系统恶性肿瘤，估计有22,350例新诊断的病例，2013年美国在美国在美国的MM死亡10,710例。MM，通常是通常的一种疾病，通常是一种疾病，通常是骨骼骨骼（BMM MM）的骨骼群体的恶性肿瘤。疾病，高钙血症，肾衰竭和/或血液功能障碍。尽管最近的治疗性进展提高了MM患者的存活率，但由于最小残留疾病的持续存在，MM仍然无法治愈。因此，迫切需要新颖的方式补充或改善当前治疗方案。有足够的证据表明免疫调节药有效地抗MM。这是一种潜在免疫治疗性的使用是一种有吸引力的方法，可以为持久的免疫血液提供给或可能治愈MM的患者。白介素15（IL-15）是效应NK细胞和CD8+记忆T细胞的发育，增殖和激活的关键因素，在动物模型中表现出针对已建立良好肿瘤的潜在抗肿瘤活性。根据其特性，NCI认为IL-15是可能治愈癌症的最有希望的免疫治疗产品候选者。我们以前已经分离出一种新型的专有IL-15突变体，其生物学活性增加。通过与IL-15受体�-IgG1融合蛋白创建复合物，进一步改善了该超级助导者IL-15（IL-15N72D）的免疫刺激特性。我们假设该复合物（称为ALT-803）的给药将引起持久，潜在和广泛的细胞介导的免疫响应，这可能会导致对MM患者的有效且潜在的治愈作用。我们的SBIR I期项目的结果支持了这种方法，表明ALT-803确实通过依赖CD8+记忆T细胞激活的新机制和来自这些T细胞的IFN-Y分泌的新机制来确立了良好的骨髓瘤肿瘤和延长肿瘤小鼠的生存率。此外，短期ALT-803治疗提供了持久的T细胞依赖性免疫学作用，这些效应完全保护小鼠免受随后的肿瘤细胞的补偿。这些研究为将ALT-803推进到针对MM的临床测试中提供了有力的理由，作为治疗方法。除SBIR I期项目外，我们还完成了动物毒理学研究和ALT-803临床产品的生产，允许FDA接受IND，以在其他癌症适应症中使用ALT-803的临床使用。在此SBIR II期提案下，我们计划进行多中心1/2期研究，以研究ALT-803的安全性，药代动力学和免疫刺激和临床活动对难治性或中继MM的患者的安全性和临床活性。这项研究的成功完成将为进一步评估ALT-803作为单一疗法或与化学疗法的进一步评估铺平道路，其中复发/难治性MM的患者的化学疗法是为了开发更耐用或治疗性治疗方法的最终目标，以进行治疗和/或中断和/或中断/或相关/差异MM患者。