IL-15 Superagonist Complex as an Immunotherapeutic for Multiple Myeloma

描述(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，2011年美国估计有20,520例新诊断病例和10,610例死亡。MM是一种老年疾病，确诊时的中位年龄为70岁，37%的患者年龄在75岁以上。随着正常人群预期寿命的延长，老年多发性骨髓瘤患者的数量预计会随着时间的推移而增加。MM是一种骨髓(BM)克隆性浆细胞的恶性肿瘤，以副蛋白血症、破坏性骨病、高钙血症、肾功能衰竭和/或血液系统功能障碍为特征。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治疗药物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患者。IL-15是效应NK细胞和CD8*记忆T细胞发育、增殖和激活的必要因素，在实验室动物模型中显示出强大的抗肿瘤活性，并被NCI最近的一项审查列为12种可能治愈癌症的免疫治疗药物中最有前途的候选产品。我们以前曾报道过一个新的IL-15突变体的分离，该突变体的生物活性增加了4倍。这种超激动型IL-15(IL-15N72D)的药代动力学和生物活性通过与IL-15受体β-IgG1融合蛋白(IL-15Rβ/Fc)形成复合体而得到进一步改善。我们推测，静脉注射IL-15N72D：IL-15R？/Fc融合复合体将提供持久、有效和广泛的细胞介导的免疫反应，这将导致一种治疗MM患者的高效且有潜在疗效的免疫疗法，这得到了我们最近研究的数据的支持，表明该IL-15融合复合体确实根除了免疫活性C57BL/6小鼠模型中已建立的5T33骨髓瘤肿瘤。更重要的是，短期治疗提供了长期的免疫效果，完全保护小鼠免受后续肿瘤细胞的再次攻击。在这里描述的这项研究中，我们建议进行实验，以揭示作用机制，并进一步评估IL-15超级激动剂诱导的对5T33肿瘤骨髓瘤的反应的持久性(免疫治疗的一个标志)。这些努力将为临床前研究铺平道路，其中将包括额外的疗效研究，以确定该复合体的最佳剂量以及药代动力学和毒理学评估，作为SBIR第二阶段项目的一部分，以支持临床开发。我们的最终目标是进入IND阶段，并使用IL-15N72D：IL-15R？/Fc超激动剂复合体治疗MM患者进行临床试验。 公共卫生相关性：在这项建议中，我们提议开展实验，以揭示作用机制，并评估新型白细胞介素15(IL-15)超激动剂复合体(IL-15N72D：IL-15R？/Fc)在5T33肿瘤多发性骨髓瘤小鼠模型中的抗肿瘤持久性(免疫治疗的一个标志)。这项拟议研究的积极结果将为这种复合体的临床开发提供理由，使其成为治疗多发性骨髓瘤患者的一种安全、持久、有效和细胞介导的免疫疗法。

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.