Novel IL-15 Superagonist Therapy for Bladder Cancer

新型 IL-15 超级激动剂治疗膀胱癌

基本信息

批准号：
9315512
负责人：
Peter R Rhode
金额：
$ 99.99万
依托单位：
ALTOR BIOSCIENCE. LLC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9315512
关键词：
Animal Model Antitumor Response BCG Vaccine Biodistribution Biological Biological Preservation Bladder Bladder Neoplasm Bladder mucosa CD8B1 gene Cancer Model Cancer Patient Carcinogens Cells Cessation of life Chimeric Proteins Clinical Clinical Trials Combined Modality Therapy Complex Development Diagnosis Disease Disease Progression Dose Drug Kinetics Evaluation Event Excision Exhibits Goals Immune Immune Cell Activation Immune response Immunocompetent Immunotherapeutic agent Immunotherapy Interferons Interleukin-15 Interleukin-2 Interleukins Intravesical Administration Malignant Neoplasms Malignant neoplasm of urinary bladder Mediator of activation protein Modeling Natural Killer Cells Oncologist Outcome Patient Care Patients Pharmaceutical Preparations Pharmacodynamics Phase Phase II Clinical Trials Phase III Clinical Trials Pre-Clinical Model Property Proteins Radical Cystectomy Randomized Rattus Recurrence Rodent Safety Small Business Innovation Research Grant Systemic Therapy T memory cell T-Lymphocyte Therapeutic Time Transurethral Resection United States animal efficacy arm base cell mediated immune response chemotherapy clinical development clinical investigation clinically relevant curative treatments cytokine disorder control experience immune activation immunogenicity improved in vivo interleukin-15 receptor intravesical mutant non-drug novel novel strategies novel therapeutics phase 2 study phase 3 study preclinical study prevent protein complex research clinical testing response standard of care tumor urologic

项目摘要

Project Summary: Bladder cancer is the fifth most common cancer in the U.S. Up to 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-Guérin (BCG) therapy. Despite treatment, up to 60% of patients will experience tumor recurrence and, of these, about 50% will undergo radical cystectomy in an attempt to control disease progression and 30% of these patients will progress and succumb to their disease. Due to its high recurrence rate, NMIBC is the costliest of all cancers to treat. Since the FDA has not approved a drug for NMIBC in the last 20 years, novel therapies are desperately needed to prevent NMIBC disease progression and allow bladder preservation. T cells and natural killer (NK) cells have been implicated as critical mediators of the antitumor immune response using BCG therapy. Interleukin-15 (IL-15), 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 stimulation and exhibits potent efficacy against tumors in various animal models. To advance IL-15-based therapies into clinical development, we have isolated a novel proprietary IL-15 superagonist mutant and associated it with an IL-15 receptor α–Fc fusion protein to generate a complex referred to as ALT-803. In numerous preclinical models, ALT-803 was shown to have improved pharmacokinetic, biodistribution and immunostimulatory properties and greater antitumor activity than IL-15 alone. 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. In clinically relevant rodent NMIBC tumor models, we found that intravesical ALT-803 + BCG therapy provided significantly better immune responses and antitumor activity than BCG monotherapy. Based on these results, a multicenter Phase 1/2 clinical trial of intravesical ALT-803 + BCG in NMIBC patients was initiated under the SBIR Phase II project and the dose escalation portion has now been successfully completed. The recommended Phase 2 dose of ALT-803 was established based on a safety profile comparable to BCG monotherapy. High-response rate with impressive durability (i.e., no disease recurrence at up to 18 months) and bladder localized immune cell activation were observed in all treated patients. These findings strongly support advancing to the randomized 2-arm dose expansion portion of the Phase 1/2 clinical trial as proposed in this Phase IIb application. In the Phase 2 study, NMIBC patients will receive intravesicular instillation of either ALT-803 + BCG or BCG alone and the disease-free response rate, duration of recurrence, and localized and systemic immune activation will be assessed. Improved clinical outcomes using ALT-803 + BCG would support a Phase 3 evaluation of intravesical ALT-803 therapy in patients with NMIBC with the ultimate goal of developing more durable or curative therapies in this indication.

项目摘要：膀胱癌是美国第五大最常见的癌症，最初是80％的患者存在局限于膀胱的粘膜。患者通过肿瘤分辨率进行治疗，然后进行静脉化疗或Calmette-guérin杆菌治疗（BCG）尽管治疗，多达60％的患者会经历肿瘤复发。 50％将在尝试控制进度的尝试中进行根本性的愤世嫉俗，其中30％将进步并融入他们的疾病。癌症治疗。迫切需要防止NMIBC疾病进展并允许保存膀胱。使用BCG的杀伤（NK）细胞已被视为抗逆数免疫反应的关键介质治疗。潜在的治愈癌是有效NK细胞NK CD8+记忆T细胞刺激的关键因素在各种动物模型中针对肿瘤的有效疗效。开发，我们已经隔离了一个新型的项目IL-15超级飞行器突变体，并将其与IL-15相关联受体α-FC融合蛋白在许多临床前模型中生成一个称为alt -803的复合物。 ALT-803已显示已改善了改进的药代动力学，生物排除和免疫稳定特性，并且仅IL-15，我们的抗杀活性更大。使用BCG将诱导耐用的细胞介导的免疫疗法，从而在患者中提供抗肿瘤功效 NMIBC。在临床上相关的啮齿动物NMIBC肿瘤模型中基于这些，预期的免疫反应和抗肿瘤活性要好结果是NMIBC患者的静脉内ALT-803 + BCG的多中心1/2期临床试验在SBIR II期项目和剂量升级部分中，部分已成功完成推荐的第2阶段ALT-803的剂量是基于与BCG相当的安全性概况而建立的单一疗法。在所有治疗的患者中都观察到膀胱局部免疫细胞活化支持前进到阶段1/2临床试验的随机2臂剂量扩展在第二阶段的IIB应用中。单独使用ALT-803 + BCG或BCG，以及无病的反应率，复发持续时间和本地将评估全身免疫激活。支持NMIBC患者的静脉内ALT-803治疗的3阶段评估，其最终目标是在此指示中开发更耐用或治愈的疗法。