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: 8781375
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781375
• 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 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; arm; base; cancer immunotherapy; cell killing; cell mediated immune response; chemotherapy; 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; public health relevance; 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层浸润性膀胱癌（NMIBC）。这些患者通过肿瘤切除术后膀胱内化疗或卡介苗（BCG）治疗。尽管治疗，60%的NMIBC患者将经历肿瘤复发，其中约30%将进展并死于疾病，而另外50%将经历根治性化疗以试图控制疾病。由于FDA在过去20年中没有批准用于NMIBC的药物，因此NMIBC迫切需要新的治疗方法来防止疾病进展并保留膀胱。NMIBC也是所有癌症中治疗成本最高的癌症，因为它的复发率很高。因此，任何针对NMIBC的有效药物都会对医疗保健成本产生很大影响。虽然导致BCG介导的功效的机制尚不清楚，但T细胞和自然杀伤（NK）细胞已被认为是抗肿瘤免疫应答的关键介质。白细胞介素-15（IL-15）以前被NCI认为是可能治愈癌症的最有前途的免疫调节剂，是效应NK细胞和CD 8+记忆T细胞增殖和活化的关键因素，在各种动物模型中对已建立的肿瘤具有高效力。为了构建IL-15的改进版本，我们已经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，以产生具有增强的药代动力学（PK）和免疫刺激特性的复合物（称为ALT- 803）。这些显著的改善最近导致NCI将ALT-803推广到天然IL-15之上，作为其对抗癌症的最佳免疫学临床候选物。我们推测，ALT-803与BCG组合的膀胱内治疗将诱导持久的细胞介导的免疫应答，从而在患有NMIBC的患者中提供抗肿瘤功效。在SBIR I期项目期间，我们发现在啮齿动物NMIBC肿瘤模型中，膀胱内ALT-803可以刺激膀胱中的免疫应答，从而产生抗肿瘤活性。此外，ALT-803 + BCG免疫疗法对致癌物诱导的NMIBC提供比BCG单一疗法显著更大的功效。这些研究表明，ALT-803 + BCG是比单独BCG更有效的治疗，并为在NMIBC患者中测试膀胱内ALT-803 + BCG治疗提供了强有力的理论基础。为了支持这些试验，我们已经完成了非临床研究和ALT-803临床产品生产，允许FDA接受用于实体瘤患者ALT-803测试的IND。根据该SBIR II期提案，我们计划进行多中心I/II期研究的剂量递增阶段，以研究膀胱内ALT-803 + BCG治疗NMIBC患者的安全性、PK、免疫刺激和临床活性。本研究的成功结果将为进一步评估NMIBC患者的膀胱内ALT-803治疗铺平道路，最终目标是为BCG初治和/或BCG难治性患者开发更持久或治愈性的治疗方法。