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

• 批准号: 8874158
• 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
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-11 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874158
• 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; Health; 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; receptor; research clinical testing; response; standard of care; success; tumor

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（由申请方提供）：多发性骨髓瘤（MM）是第二大最常诊断的血液系统恶性肿瘤，2013年在美国估计有22，350例新诊断病例和10，710例MM死亡。MM通常是老年人的疾病，是骨髓（BM）中克隆浆细胞的恶性肿瘤，其特征在于存在副蛋白血症、破坏性骨病、高钙血症、肾衰竭和/或血液学功能障碍。虽然MM患者的生存率通过最近的治疗进展有所提高，但由于微小残留病的持续存在，MM仍然无法治愈。因此，迫切需要补充或改善当前治疗选择的新模式。有充分的证据表明免疫调节药物对MM有效。因此，使用有效的免疫调节剂是一种有吸引力的方法，可以为MM患者提供持久的免疫应答，甚至可能治愈MM患者。白细胞介素-15（IL-15）是效应NK细胞和CD 8+记忆T细胞发育、增殖和活化的关键因子，在动物模型中对已确定的肿瘤表现出有效的抗肿瘤活性。基于其特性，IL-15被NCI认为是可能治愈癌症的最有前途的免疫产品候选者。我们以前已经分离出一种新的专有IL-15突变体，具有增加的生物活性。通过与IL-15受体β-IgG 1融合蛋白形成复合物，进一步提高了这种超激动剂IL-15（IL-15 N72 D）的免疫刺激特性。我们假设这个综合体的管理（称为ALT-803）将诱导持久、有效和广泛的细胞介导的免疫应答，这一方法得到了我们SBIR I期项目结果的支持，表明ALT-803确实根除了成熟的骨髓瘤肿瘤，并延长了肿瘤患者的生存期。通过依赖于CD 8+记忆T细胞的活化和IFN-γ从这些T细胞的分泌的新机制，此外，短期ALT-803治疗提供了持久的T细胞依赖性免疫效应，完全保护小鼠免受随后的肿瘤细胞再攻击。这些研究为将ALT-803作为治愈性治疗推进到针对MM的临床试验中提供了强有力的理论基础。除了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ALT-803在其他癌症适应症中临床使用的IND。根据SBIR II期提案，我们计划进行一项多中心I/II期研究，以研究安全性、药代动力学，ALT-803在难治性或复发性MM患者中的免疫刺激和临床活性。本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疗联合治疗复发性或复发性MM患者铺平道路。难治性MM，最终目标是为初治和/或复发/难治性MM患者开发更持久或治愈性的治疗选择。