Novel IL-15 Superagonist Therapy for Bladder Cancer

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，也是所有癌症中治疗费用最高的，它往往会复发，需要反复干预和长期随访。NMIBC通常采用手术切除、膀胱内化疗和免疫治疗。免疫疗法通常包括膀胱内注射卡介苗(BCG)，这是一种活的、减毒的细菌。最近一项对9项随机研究的荟萃分析证实了卡介苗膀胱内免疫治疗对于高级别NMIBC在疗效和减少疾病复发方面的优势。然而，卡介苗免疫疗法具有明显的毒性，约20%的患者未能完成整个疗程。此外，多达30%的患者要么对治疗无效，要么在5年内疾病复发。在这些人中，30%最终将死于膀胱癌，50%将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，无论是一线治疗还是抢救治疗，以防止疾病进展，并允许保留膀胱以提高患者的生活质量。尽管卡介苗治疗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反应的关键介质。IL-15是NK和CD8+记忆T细胞发育、增殖和激活所必需的因子。这种细胞因子在实验室动物模型中显示出强大的抗肿瘤活性，并被美国国家癌症研究所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。我们报道了一个新的IL-15突变体的分离，该突变体的生物活性提高了4倍。通过与IL-15受体1-IgG1融合蛋白(IL-15R1-Fc)形成复合物，进一步改善了这种超激动型IL-15(hIL-15G72D)的药代动力学和生物活性。我们推测，经尿道给药这种IL-15G72D/IL-15R1-Fc超激动剂复合物将提供持久、有效和广泛的细胞介导的免疫反应，从而导致一种比卡介苗更安全、更有效的免疫疗法来治疗NMIBC。在这项建议中，我们建议评估IL-15G72D/IL-15R1-Fc超激动剂在免疫活性小鼠NMIBC移植瘤模型中的疗效。这项可行性研究的成功将促使我们建立一个产生IL-15N72D/IL-15R1-Fc超激动剂复合体的高产细胞系，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，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-15R1-Fc超激动剂复合体对抗NMIBC进行临床试验。 公共卫生相关性： 在这项建议中，我们建议评估IL-15N72D/IL-15R1-Fc超激动剂复合体在免疫活性小鼠模型中治疗非肌肉浸润性膀胱癌(NMIBC)的疗效。这项拟议研究的积极结果将为开发IL-15N72D/IL-15R1-Fc超激动剂复合体作为一种安全、持久、有效的细胞介导性免疫疗法来取代卡介苗治疗NMIBC提供依据。

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.