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: 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
• 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

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(由申请人提供)：多发性骨髓瘤(MM)是第二种最常见的血液系统恶性肿瘤，2013年美国估计有22,350例新诊断病例和10,710例因MM而死亡。MM是一种典型的老年人疾病，是一种骨髓中克隆性浆细胞的恶性肿瘤，其特征是存在副蛋白血症、破坏性骨病、高钙血症、肾功能衰竭和/或血液系统功能障碍。尽管多发性骨髓瘤患者的存活率通过最近的治疗进展得到了改善，但由于微小残留疾病的持续存在，多发性骨髓瘤仍然是无法治愈的。因此，迫切需要新的模式来补充或改进现有的治疗方案。有充分的证据表明免疫调节药物对MM是有效的。因此，使用一种有效的免疫疗法是一种有吸引力的方法来为MM患者提供持久的免疫反应，甚至有可能治愈MM。白介素15(IL-15)是效应NK细胞和CD8+记忆T细胞发育、增殖和激活的关键因素，在动物模型中显示出强大的抗肿瘤活性。基于其特性，IL-15被NCI认为是最有希望治愈癌症的候选免疫治疗产品。我们之前已经分离到一种新的专利IL-15突变体，具有更高的生物活性。这种超激动剂IL-15(IL-15N72D)的免疫刺激特性通过与IL-15受体-IgG1融合蛋白形成复合体而得到进一步改善。我们推测，给予这种复合体(称为ALT-803)将诱导持久、有效和广泛的细胞介导的免疫反应，这可能会在MM患者中产生有效和潜在的疗效。这一方法得到了我们的SBIR第一阶段项目结果的支持，该结果表明，ALT-803确实通过一种依赖于CD8+记忆T细胞的激活和这些T细胞分泌干扰素-γ的新机制根除了成熟的骨髓瘤肿瘤，延长了荷瘤小鼠的生存时间。此外，短期的ALT-803治疗提供了长期的T细胞依赖的免疫效应，完全保护小鼠免受后续肿瘤细胞的再次攻击。这些研究为ALT-803作为一种治疗多发性骨髓瘤的临床试验提供了强有力的依据。除了SBIR第一阶段项目外，我们还完成了动物毒理学研究和ALT-803临床产品的制造，使FDA能够接受IND将ALT-803用于其他癌症适应症的临床应用。根据这项SBIR II期计划，我们计划进行一项多中心的1/2期研究，以研究ALT-803在难治性或复发性MM患者中的安全性、药代动力学、免疫刺激作用和临床活性。这项研究的成功完成将为进一步评估ALT-803作为单一疗法或联合化疗治疗复发/难治性MM患者铺平道路，最终目标是开发出更持久或更有效的治疗方案，用于治疗初治和/或复发/难治性MM患者。