Novel IL-15 Superagonist Therapy for Bladder Cancer

描述(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肉浸润性膀胱癌(NMIBC)。这些患者接受肿瘤切除、膀胱内化疗或卡介苗(BCG)治疗。尽管接受了治疗，60%的NMIBC患者仍将经历肿瘤复发，其中约30%的患者将进展并死于疾病，另有50%的患者将接受根治性膀胱切除术以试图控制疾病。由于FDA在过去20年中没有批准一种治疗NMIBC的药物，NMIBC迫切需要新的治疗方法来防止疾病进展并允许保留膀胱。由于复发率高，NMIBC也是所有癌症中治疗费用最高的。因此，任何治疗NMIBC的有效药物都将对医疗成本产生很大影响。尽管BCG介导的疗效机制尚不清楚，但T细胞和自然杀伤(NK)细胞已被认为是抗肿瘤免疫反应的关键介质。白介素15(IL-15)是多种动物模型中NK细胞和CD8+记忆T细胞高效增殖和激活的关键因子，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，我们分离了一个新的专利IL-15超级激动剂突变体，并将其与IL-15受体β-Fc融合蛋白相结合，生成具有增强的药代动力学(PK)和免疫刺激特性的复合体(称为ALT-803)。这些显著的改进导致NCI最近将ALT-803作为其抗癌免疫治疗临床候选药物的首选，而不是天然IL-15。我们推测ALT-803联合卡介苗膀胱内治疗能诱导持久的细胞免疫反应，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，膀胱内注射ALT-803可以刺激膀胱内的免疫反应，从而产生抗肿瘤活性。此外，ALT-803+卡介苗免疫治疗对致癌物诱导的NMIBC的疗效明显优于卡介苗单一治疗。这些研究表明，ALT-803+BCG是一种比单独使用BCG更有效的治疗方法，并为测试ALT-803+BCG膀胱内注射疗法治疗NMIBC提供了强有力的理论依据。为了支持这样的试验，我们已经完成了非临床研究和ALT-803临床产品制造，允许FDA接受IND用于实体瘤患者的ALT-803测试。根据这项SBIR第二阶段建议，我们计划进行一项多中心第1/2阶段研究的剂量递增阶段，以调查ALT-803+卡介苗膀胱内注射治疗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NMIBC患者的膀胱内ALT-803疗法铺平道路，最终目标是为BCG-NA和/或BCG耐药患者开发更持久或更有效的疗法。

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.