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: 8910664
• 负责人: HING C. WONG
• 金额: $ 59.83万
• 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 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910664
• 关键词: Amendment; Animal Cancer Model; Animal Model; Bacillus (bacterium); Biodistribution; Biological; Biological Preservation; Bladder; Bladder Neoplasm; Bladder mucosa; CD8B1 gene; Cancer Model; Cancer Patient; Carcinogens; Cells; Cessation of life; Chimeric Proteins; Clinical; Clinical Protocols; Clinical Trials; Complex; Cyclic GMP; Development; Diagnosis; Disease; Disease Progression; Dose; Drug Kinetics; Evaluation; Excision; Exhibits; Goals; Health; Health Care Costs; Immune; Immune response; Immunocompetent; Immunotherapeutic agent; Immunotherapy; Infiltration; Interferons; Interleukin-15; Interleukin-2; Interleukins; Intravesical Administration; Laboratory Animals; Lead; Macaca fascicularis; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Maximum Tolerated Dose; Mediating; Mediator of activation protein; Memory; Metastatic Melanoma; Modeling; Mus; Natural Killer Cells; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase III Clinical Trials; Property; Radical Cystectomy; Randomized; Rattus; Recurrence; Refractory; Rodent; Safety; Small Business Innovation Research Grant; Solid Neoplasm; T cell response; T memory cell; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Toxicology; Transurethral Resection; United States; Urothelium; antitumor effect; arm; base; cancer immunotherapy; cell killing; cell mediated immune response; chemotherapy; clinical investigation; cytokine; disorder control; effective therapy; experience; immunogenicity; improved; in vivo; interleukin-15 receptor; intravesical; mutant; neoplastic cell; non-drug; novel; novel strategies; phase 2 study; preclinical study; prevent; protein complex; receptor; research clinical testing; response; success; tumor

DESCRIPTION (provided by applicant): Bladder cancer is the fifth most common cancer in the United States. Over 70 - 80% of patients initially present with non-muscle invasive bladder cancer (NMIBC) confined to the mucosa of the bladder. These patients are treated by tumor resection followed by intravesical chemotherapy or Bacillus Calmette-Gu�rin (BCG) therapy. Despite treatment, 60% of NMIBC patients will experience tumor recurrence and, of these, ~30% will progress and succumb to their disease while another 50% will undergo radical cystectomy in an attempt at disease control. Since the FDA has not approved a drug for NMIBC in the last 20 years, novel therapies are desperately needed for NMIBC to prevent disease progression and allow bladder preservation. NMIBC is also the costliest of all cancers to treat due to its high recurrence rate. Thus, any effective drug for NMIBC will have a large impact on healthcare costs. Although the mechanisms leading to BCG-mediated efficacy are unclear, T cells and natural killer (NK) cells have been implicated as critical mediators of the antitumor immune response. Interleukin-15 (IL-15), previously considered by the NCI as the most promising immunotherapeutic that could potentially cure cancer, is a crucial factor for effector NK cell and CD8+ memory T cell proliferation and activation with high potency against established tumors in various animal models. To construct an improved version of IL-15, we have isolated a novel proprietary IL-15 superagonist mutant and associated it with an IL-15 receptor �-Fc fusion protein to generate a complex (referred to as ALT- 803) with enhanced pharmacokinetic (PK) and immunostimulatory properties. These significant improvements have recently led NCI to promote ALT-803 over native IL-15 as its top immunotherapeutic clinical candidate against cancer. We postulate that intravesical treatment of ALT-803 in combination with BCG will induce durable cell-mediated immune responses providing antitumor efficacy in patients with NMIBC. During the SBIR Phase I project, we found that in rodent NMIBC tumor models, intravesical ALT-803 could stimulate immune responses in the bladder leading to antitumor activity. Moreover, ALT-803 + BCG immunotherapy provided significantly greater efficacy than BCG monotherapy against carcinogen-induced NMIBC. These studies suggest that ALT-803 + BCG is a more effective treatment than BCG alone and provide a strong rationale for testing intravesical ALT-803 + BCG therapy in patients with NMIBC. To support such trials, we have completed non-clinical studies and ALT-803 clinical product manufacture allowing FDA acceptance of an IND for ALT-803 testing in patients with solid tumors. Under this SBIR Phase II proposal, we plan to conduct a dose escalation phase of a multicenter Phase 1/2 study to investigate the safety, PK, and immunostimulatory and clinical activities of intravesical ALT-803 + BCG treatment in patients with NMIBC. Successful outcomes in this study will pave the way for further evaluation of intravesical ALT-803 therapy in patients with NMIBC with the ultimate goal of developing more durable or curative therapies for BCG-na�ve and/or BCG-refractory patients.

描述（由申请人提供）：膀胱癌是美国第五大常见癌症。超过70 - 80%的患者最初表现为局限于膀胱粘膜的非肌性浸润性膀胱癌（NMIBC）。这些患者接受肿瘤切除后膀胱内化疗或卡介苗（BCG）治疗。尽管接受了治疗，但60%的NMIBC患者会经历肿瘤复发，其中约30%会进展并死于疾病，而另外50%将接受根治性膀胱切除术以试图控制疾病。由于FDA在过去的20年里没有批准用于NMIBC的药物，因此迫切需要新的治疗方法来预防NMIBC的疾病进展并允许膀胱保存。NMIBC也是所有癌症中治疗费用最高的，因为它的复发率很高。因此，任何治疗NMIBC的有效药物都会对医疗成本产生很大影响。虽然导致bcg介导的疗效的机制尚不清楚，但T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。在各种动物模型中，白细胞介素-15 （IL-15）是效应NK细胞和CD8+记忆T细胞高效增殖和激活肿瘤的关键因素，此前被NCI认为是最有希望治愈癌症的免疫治疗药物。为了构建IL-15的改进版本，我们分离了一种新的专有IL-15超激动剂突变体，并将其与IL-15受体- fc融合蛋白结合，产生具有增强药代动力学（PK）和免疫刺激特性的复合物（称为ALT- 803）。这些显著的改进最近促使NCI将ALT-803推荐给天然IL-15，作为其抗癌免疫治疗的首选临床候选药物。我们假设ALT-803膀胱内治疗联合卡介苗将诱导持久的细胞介导免疫应答，为NMIBC患者提供抗肿瘤疗效。在SBIR一期项目中，我们发现在啮齿动物NMIBC肿瘤模型中，膀胱内ALT-803可以刺激膀胱的免疫反应，从而产生抗肿瘤活性。此外，ALT-803 + BCG免疫治疗对致癌物诱导的NMIBC的疗效明显高于BCG单药治疗。这些研究表明，ALT-803 +卡介苗治疗比单独使用卡介苗更有效，并为在NMIBC患者中测试膀胱内ALT-803 +卡介苗治疗提供了强有力的理论依据。为了支持这些试验，我们已经完成了非临床研究和ALT-803临床产品的生产，允许FDA接受ALT-803在实体瘤患者中的测试。根据SBIR II期提案，我们计划开展一项多中心1/2期剂量递增期研究，以研究ALT-803 + BCG膀胱内治疗NMIBC患者的安全性、PK、免疫刺激和临床活性。这项研究的成功结果将为进一步评估膀胱内ALT-803治疗NMIBC患者铺平道路，最终目标是为bcg初始和/或bcg难治性患者开发更持久或治愈性的治疗方法。