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：
8392994
负责人：
HING C. WONG
金额：
$ 23.19万
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8392994
关键词：
Adoptive Cell Transfers Adrenal Cortex Hormones Age Apoptosis Apoptotic Autologous Stem Cell Transplantation Biological Bone Diseases Bone Marrow Bortezomib C57BL/6 Mouse CD8-Positive T-Lymphocytes CD8B1 gene Cell Adhesion Molecules Cells Cessation of life Chimeric Proteins Clinical Comorbidity Complement Complex Conduct Clinical Trials Data Development Dexamethasone Diagnosis Disease Disease remission Dose Doxorubicin Drug Kinetics Effectiveness Effector Cell Elderly Evaluation Exhibits Flow Cytometry Functional disorder Goals Growth Growth Factor Hematologic Neoplasms Hypercalcemia IgG1 Immune response Immunity Immunocompetent Immunotherapeutic agent Immunotherapy Infusion procedures Insulin-Like Growth Factor I Integrins Interleukin-15 Interleukin-2 Interleukin-6 Kidney Failure Kinetics Laboratory Animal Models Life Expectancy Malignant Neoplasms Mediating Modality Modeling Multiple Myeloma Mus Natural Killer Cells Newly Diagnosed Outcome Paraproteinemias Patients Pattern Pharmaceutical Preparations Phase Plasma Cells Play Population Production Proteasome Inhibitor Reporting Residual Neoplasm Resistance Role Small Business Innovation Research Grant Survival Rate T memory cell T-Lymphocyte TNF gene Thalidomide Therapeutic Time Toxic effect Toxicology United States Vascular Endothelial Growth Factors Vincristine analog base cell growth cell mediated immune response chemotherapy cytokine improved interleukin-15 receptor intravenous administration lenalidomide mouse model mutant neoplastic cell novel older patient preclinical study research study response standard of care treatment response tumor

项目摘要

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy with an estimated 20,520 newly diagnosed cases and 10,610 deaths due to MM in the United States in 2011. MM is a disease of the elderly with a median age at diagnosis of 70 years and 37% of patients older than 75 years. The number of geriatric MM patients is expected to increase over time because of the increasing life expectancy of the normal population. MM 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. Thus, 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. IL-15, a necessary 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 laboratory animal models and is listed by a recent NCI review as the most promising product candidate among twelve immunotherapy drugs that could potentially cure cancer. We have previously reported the isolation of a novel IL-15 mutant with a 4-fold increase in biological activity. The pharmacokinetics and biological activity of this superagonistic IL-15 (IL-15N72D) have been further improved by creating a complex with an IL-15 receptor ¿ - IgG1 fusion protein (IL-15R¿/Fc). We postulate that that intravenous administration of the IL-15N72D:IL- 15R¿/Fc fusion complex will provide a durable, potent and broad cell-mediated immune response, which would result in a highly efficacious and potentially curative immunotherapy for the treatment of patients with MM. This is supported by the data from our recent studies, indicating that this IL-15 fusion complex indeed eradicated well-established 5T33 myeloma tumors in an immunocompetent C57BL/6 mouse model. More importantly, short-term treatment provided long-lasting immunological effects that completely protected mice against subsequent tumor cell rechallenge. In this study described here, we propose to carry out experiments to reveal the mechanisms of action and to further evaluate the durability (a hallmark of immunotherapy) of IL- 15 superagonist-induced responses for 5T33 tumor-based myeloma in mice. These efforts will pave the way for pre-clinical studies, which will include additional efficacy studies to determine optimal dosing and pharmacokinetics and toxicology evaluation of the complex, as part of the SBIR Phase II project, to support clinical development. Our ultimate goal is to enter the IND phase and to conduct clinical trials using the IL- 15N72D:IL-15R¿/Fc superagonist complex to treat patients with MM. PUBLIC HEALTH RELEVANCE: In this proposal, we propose to carry out experiments to reveal the mechanisms-of-action and to evaluate the anti-tumor durability (a hallmark of immunotherapy) of a novel interleukin-15 (IL-15) superagonist complex (IL- 15N72D:IL-15R¿/Fc) in the 5T33 tumor-based multiple myeloma model in mice. Positive outcomes from this proposed study would provide justification for clinical development of this complex as a safe, durable, potent and cell-mediated immunotherapy to treat patients with multiple myeloma.

描述（由适用提供）：多发性骨髓瘤（MM）是第二个常见的血液系统恶性肿瘤，估计有20,520例新诊断病例，2011年在美国在美国毫米造成的10,610例死亡。MM是一种较早的患者，患者的中位年龄为70岁，年龄在75岁以上的疾病。由于正常人群的预期寿命增加，老年MM患者的数量预计会随着时间的推移增加。 MM是骨髓（BM）中克隆浆细胞的恶性肿瘤，其特征是存在少量蛋白质血症，破坏性骨病，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。这是完成或改进的新型方式，有足够的证据表明免疫调节药物对MM有效。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。 IL-15是效应NK细胞和CD8*记忆T细胞的开发，增殖和激活的必要因素，它在实验室动物模型中表现出了针对已建立的肿瘤的潜在抗肿瘤活性，最近的NCI综述列出了NCI综述，这是在12种潜在可治疗癌症的十二种免疫疗法药物中最有前途的产品候选者。我们先前已经报道了新型IL-15突变体的分离，生物学活性增加了4倍。通过与IL-15受体�-IgG1融合蛋白（IL-15R¿/FC）创建复合物，该超振源性IL-15（IL-15N72D）的药代动力学和生物学活性得到了进一步改善。我们假设IL-15N72D：IL-15R¿ /FC融合复合物的静脉内给药将提供持久，潜在和广泛的细胞介导的免疫响应，这将导致高效且潜在的现代免疫疗法来治疗MM患者。这是我们最近研究的数据支持的，表明这种IL-15融合复合物确实在免疫能力的C57BL/6小鼠模型中确实放射了良好的5T33骨髓瘤肿瘤。更重要的是，短期治疗提供了持久的免疫学作用，使小鼠完全保护了随后的肿瘤细胞补偿。在此处描述的这项研究中，我们建议进行实验，以揭示作用机制，并进一步评估IL-15超级飞机诱导的小鼠5T33肿瘤骨髓瘤的耐用性（免疫疗法的标志）。这些努力将为临床前研究铺平道路，其中将包括其他有效性研究，以确定该复合物作为SBIR II期项目的一部分，以确定该复合物的最佳剂量和药代动力学和毒理学评估，以支持临床发展。我们的最终目标是进入IND阶段，并使用IL-15N72D：IL-15R€ /FC超级飞机综合体进行临床试验，以治疗MM的患者。公共卫生相关性：在这项提议中，我们建议进行实验，以揭示行动机制，并评估一种新型的白介素15（IL-15）超级飞行器复合物（IL-15N72D：IL-15N72D：IL-15R：IL-15R？/fc）的抗肿瘤耐用性（免疫疗法的标志）在5T33 TAMOR基型Mouldermoma中。这项拟议的研究的积极结果将为这种复合物的临床发展提供理由，作为一种安全，耐用，潜在和细胞介导的免疫疗法，以治疗多发性骨髓瘤患者。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor αSu/Fc fusion complex in syngeneic murine models of multiple myeloma.

DOI：
10.1158/0008-5472.can-12-2357
发表时间：
2013-05-15
期刊：
Cancer research
影响因子：
11.2
作者：
Xu W;Jones M;Liu B;Zhu X;Johnson CB;Edwards AC;Kong L;Jeng EK;Han K;Marcus WD;Rubinstein MP;Rhode PR;Wong HC
通讯作者：
Wong HC