Novel IL-15 Superagonist Therapy for Bladder Cancer

新型 IL-15 超级激动剂治疗膀胱癌

• 批准号: 8195384
• 负责人: HING C. WONG
• 金额: $ 22.53万
• 依托单位: ALTOR BIOSCIENCE. LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195384
• 关键词: Adverse effects; Animal Model; Attenuated; Bacteria; Biological; Biological Markers; Biological Preservation; Bladder; Bladder Neoplasm; CD8B1 gene; Calmette-Guerin Bacillus; Cancer Patient; Cell Line; Cells; Cessation of life; Chimeric Proteins; Chitosan; Clinical; Clinical Research; Complex; Conduct Clinical Trials; Development; Disease; Disease Progression; Dose; Drug Kinetics; Evaluation; Excision; Exhibits; Expenditure; Feasibility Studies; Goals; IgG1; Immune; Immune response; Immunocompetent; Immunotherapy; Implant; Interleukin-15; Interleukin-6; Intervention; Intravesical Administration; Laboratory Animal Models; Life; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Mediator of activation protein; Medical; Meta-Analysis; Mitomycins; Modeling; Mus; Muscle; Operative Surgical Procedures; Outcome; Patients; Pharmaceutical Preparations; Phase; Procedures; Production; Quality of life; Radical Cystectomy; Randomized; Recurrence; Reporting; Rodent Model; Salvage Therapy; Serum; Small Business Innovation Research Grant; T memory cell; T-Lymphocyte and Natural Killer Cell; Testing; Time; Toxic effect; Toxicology; United States; Urothelium; cell mediated immune response; chemotherapy; clinical efficacy; cytokine; efficacy testing; follow-up; improved; interleukin-15 receptor; intravesical; macrophage; mouse model; mutant; novel; preclinical study; prevent; protein complex; receptor; success; tumor

DESCRIPTION (provided by applicant): Non-Muscle Invasive Bladder cancer (NMIBC), the fifth most common cancer in the United States and the costliest to treat per patient of all cancers, tends to recur, requiring repeated intervention and long-term follow-up. NMIBC are usually treated by surgical resection and intravesical chemotherapy and immunotherapy. Immunotherapy usually consists of intravesical administration of Bacillus Calmette-Guerin (BCG), a live, attenuated bacterium. A recent meta-analysis of nine randomized studies confirmed the superiority of intravesical immunotherapy with BCG for high-grade NMIBC both in terms of efficacy and decreasing disease recurrence. However, BCG immunotherapy is associated with significant toxicity, and approximately 20 percent of patients fail to complete the course of therapy. In addition, as many as 30 percent of patients either fail to respond to therapy or suffer disease recurrence within 5 years. Of these, 30 percent will eventually die of bladder cancer and 50 percent will undergo radical cystectomy. Thus, a novel therapy, either as first-line or salvage therapy, is desperately needed for NMIBC to prevent disease progression and allow for bladder preservation to improve quality of life of patients. Although the mechanism of action for BCG therapy leading to clinical efficacy is unclear, T lymphocytes and natural killer (NK) cells are implicated as the critical mediators of the anti-tumor immune response. IL-15 is a necessary factor for the development, proliferation and activation of effector NK and CD8+ memory T cells. This cytokine 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 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 (hIL-15G72D) have been further improved by creating a complex with an IL-15 receptor 1 - IgG1 fusion protein (IL-15R1-Fc). We postulate that transurethral administration of this IL-15G72D/IL-15R1-Fc superagonistic complex will provide a durable, potent and broad cell-mediated immune responses which would result in a safer and more efficacious immunotherapy than that of BCG for the treatment of patients with NMIBC. In this proposal, we propose to evaluate the efficacy of the IL-15G72D/IL-15R1-Fc superagonist in an implanted NMIBC tumor model in immunocompetent mice. Success of this proposed feasibility study will prompt us to create a high-production cell line for generating IL-15N72D/IL-15R1-Fc superagonist complex and to further refine the purification procedure. 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-15R1-Fc superagonist complex against NMIBC. PUBLIC HEALTH RELEVANCE: In this proposal, we propose to evaluate the efficacy of the IL-15N72D/IL-15R1-Fc superagonist complex against non-muscle invasive bladder cancer (NMIBC) in an immunocompetent mouse model. Positive outcomes from this proposed study would provide justification for developing IL-15N72D/IL-15R1-Fc superagonistic complex as a safe, durable, potent and cell-mediated immunotherapy to replace Bacillus Calmette-Guerin for the treatment of patients with NMIBC.

描述（由申请人提供）： 非肌肉浸润性膀胱癌（NMIBC）是美国第五大常见癌症，也是所有癌症中每位患者治疗成本最高的癌症，往往会复发，需要反复干预和长期随访。NMIBC通常通过手术切除和膀胱内化疗和免疫治疗来治疗。免疫疗法通常包括膀胱内施用卡介苗（BCG），一种减毒活细菌。最近对9项随机研究的荟萃分析证实了BCG膀胱内免疫治疗在疗效和降低疾病复发方面对高级别NMIBC的优越性。然而，BCG免疫疗法与显著的毒性相关，大约20%的患者未能完成疗程。此外，多达30%的患者要么对治疗无效，要么在5年内复发。其中，30%的人最终会死于膀胱癌，50%的人会接受根治性膀胱切除术。因此，NMIBC迫切需要一种新的治疗方法，无论是作为一线治疗还是挽救治疗，以防止疾病进展并允许保留膀胱以改善患者的生活质量。虽然BCG治疗导致临床疗效的作用机制尚不清楚，但T淋巴细胞和自然杀伤（NK）细胞被认为是抗肿瘤免疫应答的关键介质。IL-15是效应NK和CD 8+记忆T细胞发育、增殖和活化的必要因子。这种细胞因子在实验室动物模型中对已建立的肿瘤表现出有效的抗肿瘤活性，并被最近的NCI审查列为可能治愈癌症的12种免疫治疗药物中最有前途的候选产品。我们已经报道了一种新的IL-15突变体的分离，其生物活性增加了4倍。通过与IL-15受体1 -IgG 1融合蛋白（IL-15 R1-Fc）形成复合物，进一步改善了这种超激动性IL-15（hIL-15 G72 D）的药代动力学和生物活性。我们推测，经尿道给予这种IL-15 G72 D/IL-15 R1-Fc超激动复合物将提供持久、有效和广泛的细胞介导的免疫应答，这将导致比BCG更安全和更有效的免疫疗法用于治疗NMIBC患者。在该提议中，我们提议在免疫活性小鼠中的植入NMIBC肿瘤模型中评估IL-15 G72 D/IL-15 R1-Fc超激动剂的功效。该可行性研究的成功将促使我们创建用于产生IL-15 N72 D/IL-15 R1-Fc超激动剂复合物的高产细胞系，并进一步完善纯化程序。这些努力将为临床前研究铺平道路，这些研究将包括额外的疗效研究，以确定复合物的最佳剂量和药代动力学和毒理学评价，作为SBIR II期项目的一部分，以支持临床开发。我们的最终目标是进入IND阶段，并使用IL-15 N72 D/IL-15 R1-Fc超激动剂复合物针对NMIBC进行临床试验。 公共卫生相关性： 在该提案中，我们提出在免疫活性小鼠模型中评估IL-15 N72 D/IL-15 R1-Fc超激动剂复合物对非肌肉浸润性膀胱癌（NMIBC）的功效。这项拟议研究的积极结果将为开发IL-15 N72 D/IL-15 R1-Fc超激动复合物作为一种安全、持久、有效和细胞介导的免疫疗法以取代卡介苗治疗NMIBC患者提供依据。

项目成果

IL-15:IL-15 receptor alpha superagonist complex: high-level co-expression in recombinant mammalian cells, purification and characterization.

• DOI: 10.1016/j.cyto.2011.09.028
• 发表时间: 2011-12
• 期刊: CYTOKINE
• 影响因子: 3.8
• 作者: Han, Kai-Ping;Zhu, Xiaoyun;Liu, Bai;Jeng, Emily;Kong, Lin;Yovandich, Jason L.;Vyas, Vinay V.;Marcus, Warren D.;Chavaillaz, Pierre-Andre;Romero, Christian A.;Rhode, Peter R.;Wong, Hing C.
• 通讯作者: Wong, Hing C.