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

新型超级激动剂 IL-15 复合物和抗 CD20 抗体联合免疫疗法治疗惰性非霍奇金淋巴瘤

基本信息

批准号：
9048917
负责人：
HING C. WONG
金额：
$ 96.18万
依托单位：
ALTOR BIOSCIENCE. LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2017-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9048917
关键词：
Activated Natural Killer Cell Adoptive Transfer Adverse effects Affect Age Animal Model B lymphoid malignancy B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes Biodistribution Biological Bone Marrow CD8B1 gene Cancer Patient Caring Cell Line Cell Proliferation Cell physiology Cells Cessation of life Chimeric Proteins Clinical Clinical Protocols Clinical Research Clinical Trials Complex Development Diagnosis Disease Dose Drug Kinetics Effector Cell Elderly Evaluation Exhibits FDA approved Feasibility Studies Follicular Lymphoma Goals Granzyme Hematologic Neoplasms Human Human Activities IgG1 Immune Immune response Immunotherapeutic agent Immunotherapy In Vitro Indolent Infusion procedures Institutional Review Boards Interleukin-15 Laboratory Animal Models Lymphoma MS4A1 gene Malignant Neoplasms Mediating Minnesota Modeling Mus NK Cell Activation Natural Killer Cells Non-Hodgkin&apos s Lymphoma Organ Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phase II Clinical Trials Play Positioning Attribute Property Proteins Recurrence Refractory Regimen Relapse Reporting Research Role SCID Mice Safety Small Business Innovation Research Grant Solid Neoplasm Staging T memory cell Therapeutic Therapeutic antibodies Time Toxic effect United States Universities Washington advanced disease antibody-dependent cell cytotoxicity base cell growth chemotherapy cytokine effective therapy improved in vivo interleukin-15 receptor mutant novel perforin phase 2 study preclinical study protein complex public health relevance research clinical testing rituximab tositumomab tumor

项目摘要

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.

描述（由适用提供）：非霍奇金淋巴瘤（NHL）是美国最常见的血液系统恶性肿瘤，患有超过70,000例新病例，由于预计2015年的NHL而导致的19,000例死亡。所有病例在2015年预计。超过三分之一的病例是生长缓慢或不稳固的NHL（INHL（INHL）），影响老年人和典型疾病。 INHL的初始治疗方法由单独或与化学疗法结合使用的抗CD20抗体（利妥昔单抗）组成。尽管一线疗法在大多数患者中都是有效的，但它们不是治愈性的，由于化疗而导致的长期并发症是主要问题。这是需要有效，耐用且耐受良好的INHL治疗方法。由于利妥昔单抗的抗肿瘤活性部分取决于天然杀伤（NK）细胞的抗体依赖性细胞介导的细胞毒性（ADCC）的机理，因此已经提出，免疫治疗剂可以增强这些细胞的功能，还可以增强Rituximab热活性。白介素15（IL-15），这是效应nk细胞发展，增殖和激活的关键因素和CD8+记忆T细胞，在动物模型中表现出针对已建立肿瘤的潜在抗肿瘤活性。根据其特性，NCI认为IL-15是可能治愈癌症的最有希望的免疫治疗产品候选者。我们已经产生了一种新型的专有IL-15突变体，其生物学活性增加。通过与IL-15受体α-IgG1融合蛋白创建复合物，进一步改善了该超级方位肌IL-15的免疫刺激特性。目前，该IL-15超级方位络合物（称为ALT-803）目前正在进行的四项IND支持研究中，对血液学和实体瘤患者进行了研究。这些研究的最初结果表明，ALT-803可以用能够诱导NK细胞增殖和细胞因子释放的剂量给患者施用，而不会引起明显的毒性，我们假设Alt-803与利妥昔单抗结合使用耐用性，可诱导潜在的抗肿瘤免疫疗法，这可能会导致潜在的治疗效率，这可能会在患者中可治愈。我们的可行性研究结果支持了这种方法，表明在体外ALT-803激活人NK细胞可以增强对人CD20+ B细胞淋巴瘤细胞系和原发性人淋巴瘤细胞的利妥昔单抗指导的ADCC。在两个效率模型中进一步验证了这些结果，表明ALT-803加列妥昔单抗免疫疗法提供了比含有人淋巴瘤细胞的小鼠中的ALT-803或单独的ALT-803或Rituximab更大的NK细胞抗肿瘤活性和更长的生存率。这些研究为将ALT-803加上利妥昔单抗推进到反传递或难治性（RER/REF）INHL的临床测试中提供了有力的理由。在此SBIR II期建议下，我们计划进行多中心1/2期研究，以研究ALT-803与Rituximab在REL/REF INHL患者中结合利妥昔单抗的安全性，药代动力学以及免疫刺激和临床活性。成功完成拟议的研究将为其他B细胞恶性肿瘤中的利妥昔单抗和其他批准的治疗抗体在其他恶性肿瘤中进一步评估ALT-803的进一步评估。