Combination Immunotherapy of a Novel Superagonist IL-15 Complex and Anti-CD20 Antibody for Indolent Non-Hodgkin Lymphoma

 描述(由申请人提供)：非霍奇金淋巴瘤(NHL)是美国最常见的血液系统恶性肿瘤，预计2015年将有超过70,000例新病例和约19,000人死于NHL。超过三分之一的病例是生长缓慢或迟钝的非霍奇金淋巴瘤(INHL)，影响老年人，通常表现为晚期疾病。INHL的最初治疗包括单独或联合化疗的抗CD20抗体(利妥昔单抗)。尽管一线疗法对大多数患者有效，但它们并不能治愈，化疗引起的长期并发症是一个主要问题。因此，需要对iNHL进行有效、持久和耐受性良好的治疗。由于利妥昔单抗的抗肿瘤活性部分依赖于自然杀伤(NK)细胞产生的抗体依赖的细胞介导的细胞毒作用(ADCC)机制，因此认为增强这些细胞功能的免疫治疗剂也可能增强利妥昔单抗的治疗活性。IL-15在效应NK细胞发育、增殖和激活中的作用 和CD8+记忆T细胞，在动物模型中显示出强大的抗肿瘤活性。基于其特性，IL-15被NCI认为是最有希望治愈癌症的候选免疫治疗产品。我们已经产生了一种新的专利IL-15突变体，具有更高的生物活性。这种超级激动剂IL-15的免疫刺激特性通过创建与IL-15受体α-IgG1融合蛋白的复合体而得到进一步改善。这种IL-15超级激动剂复合体(称为ALT-803)目前正在进行四项由IND支持的研究，用于血液和实体肿瘤患者。这些研究的初步结果表明，ALT-803可以在不引起明显毒性的情况下，以能够诱导NK细胞增殖和细胞因子释放的剂量应用于患者。我们推测，ALT-803与利妥昔单抗联合使用将诱导持久、有效的抗肿瘤免疫反应，这可能会对iNHL患者产生潜在的疗效。我们的可行性研究结果表明，体外激活人NK细胞的ALT-803可以增强利妥昔单抗对人CD20+B细胞淋巴瘤细胞株和原代人淋巴瘤细胞的ADCC作用。这些结果在两个疗效模型中得到了进一步验证，表明ALT-803联合利妥昔单抗免疫疗法在荷人淋巴瘤细胞的小鼠中比单独使用ALT-803或利妥昔单抗具有更强的NK细胞抗肿瘤活性和更长的生存期。这些研究为将ALT-803联合利妥昔单抗用于治疗复发或难治性(REL/REF)iNHL的临床试验提供了强有力的理由。根据这项SBIR第二阶段计划，我们计划进行一项多中心第1/2阶段研究，以调查ALT-803联合利妥昔单抗治疗REL/REF iNHL患者的安全性、药代动力学、免疫刺激活性和临床活性。这项拟议研究的成功完成将为进一步评估ALT-803与利妥昔单抗联合用于其他B细胞恶性肿瘤以及与其他经批准的治疗性抗体联合用于其他恶性肿瘤铺平道路。

 DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) is the most commonly diagnosed hematologic malignancy in the U.S. with over 70,000 new cases and about 19,000 deaths due to NHL expected in 2015. Over one third of all cases are slow-growing or indolent NHL (iNHL) which affect older adults and typically present as advanced disease. The initial treatment of iNHL consists of an anti-CD20 antibody (rituximab) alone or in combination with chemotherapy. Although first-line therapies are effective in most patients, they are not curative and long- term complications due to chemotherapy are a major concern. Thus, there is a need for effective, durable and well-tolerated treatments for iNHL. Since the antitumor activity of rituximab relies in part on the mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells, it has been suggested that immunotherapeutic agents which enhance the function of these cells may also augment rituximab therapeutic activity. Interleukin-15 (IL-15), a crucial factor for the development, proliferation and activation of effector NK cells and CD8+ memory T cells, exhibits potent antitumor activities against established tumors in animal models. Based on its properties, IL-15 is considered by NCI as the most promising immunotherapeutic product candidate that could potentially cure cancer. We have generated a novel proprietary IL-15 mutant with increased biological activity. The immunostimulatory properties of this superagonist IL-15 was further improved by creating a complex with an IL-15 receptor α-IgG1 fusion protein. This IL-15 superagonist complex (referred to as ALT-803) is currently in four ongoing IND-supported studies in patients with hematologic and solid tumors. Initial results from these studies indicate that ALT-803 can be administered to patients at a dose capable of inducing NK cell proliferation and cytokine release without causing significant toxicity We postulate that ALT-803 in combination with rituximab will induce durable, potent antitumor immune responses, which could result in potentially curative efficacy in patients with iNHL. This approach is supported by results of our feasibility studies indicating that ALT-803 activation of human NK cells in vitro can enhance rituximab-directed ADCC against human CD20+ B cell lymphoma cell lines and primary human lymphoma cells. These results were further verified in two efficacy models showing that ALT-803 plus rituximab immunotherapy provided greater NK cell antitumor activity and longer survival than either ALT-803 or rituximab alone in mice bearing human lymphoma cells. These studies provide a strong rationale for advancing ALT-803 plus rituximab into clinical testing against relapsed or refractory (rel/ref) iNHL. Under this SBIR Phase II proposal, we plan to conduct a multicenter Phase 1/2 study to investigate the safety, pharmacokinetics, and immunostimulatory and clinical activities of ALT-803 in combination with rituximab in patients with rel/ref iNHL. Successful completion of the proposed study will pave the way for further evaluation of ALT-803 in combination with rituximab in other B cell malignancies and with other approved therapeutic antibodies in other malignancies.