Phase I study humanized 3F8 MoAb (IND 112594) and NK cells (IND BB-13399) for neuroblastoma

人源化 3F8 MoAb (IND 112594) 和 NK 细胞 (IND BB-13399) 治疗神经母细胞瘤的 I 期研究

• 批准号: 9488351
• 负责人: KATHARINE C HSU
• 金额: $ 24.99万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9488351
• 关键词: Phase; study; humanized; 3F8; MoAb

PROJECT SUMMARY/ABSTRACT Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. While intensive induction chemotherapy and aggressive surgery have improved remission rates in young patients, results have been less impressive in older patients and in the 40% of patients with chemoresistant NB. Metastatic NB in children > 18 months of age at diagnosis carries a long-term relapse-free survival of only ~20%. These disappointing results are compelling reasons for pursuing novel therapeutic approaches. One alternative approach has been immunotherapy with murine 3F8, an IgG3 monoclonal antibody to the GD2 glycolipid antigen ubiquitously present on NB cells. Its major disadvantage, however, is the development of neutralizing antibodies, which can limit its effectiveness. 3F8 administration can confer a survival benefit to NB patients in remission, but it is not effective for patients with resistant soft tissue NB or patients with progressive disease. This may be due in part to its dependence on antibody-dependent cell-mediated cytotoxicity (ADCC), the latter mediated largely by natural killer (NK) cells, which are depleted in heavily pre-treated patients. Adoptive transfer of NK cells from a healthy allogeneic source can restore and enhance 3F8 effects in these poor-risk patients. Natural killer (NK) cells are lymphocytes that have the capacity for antitumor activity via multiple pathways, including ADCC through engagement of the CD16 Fc receptor. The capacity of an NK cell for cytotoxic response, however, is dictated by its cell surface receptors, specifically the inhibitory killer-Ig like receptors (KIR) that are specific for self-MHC class I molecules. To maximize the effects of adoptively transferred NK cells, one should select donors from whom there is the greatest likelihood of engendering NK alloreactivity and of achieving highest functional NK response. This can be accomplished by selecting donors based on the HLA and KIR genotypes of the donor and the patient. This proposal presents a novel immunotherapeutic approach for the treatment of high-risk neuroblastoma. The combination of 3F8 monoclonal antibody with adoptively transferred NK cells from appropriately selected donors should increase ADCC, antibody efficacy, and tumor eradication. The availability of a highly effective humanized 3F8 antibody may increase tumor response while avoiding the development of neutralizing antibodies that are so common to murine analogs. Because these immunologic approaches have never been studied in combination for a solid tumor or in the pediatric population, a phase I study to examine the safety of humanized 3F8 combined with escalating doses of NK cells is necessary and represents the first aim of the proposal. Potential toxicities of NK and 3F8 therapies, a toxicity monitoring plan, dose escalation plan, the expected outcome and stopping rules are presented. The second aim seeks to correlate donor-recipient KIR/HLA immunogenetics and donor FcR polymorphism with (1) NK activation and cytotoxic function against NB target cells in vitro, and (2) with patient response to treatment. Demonstration of safety and feasibility of combining adoptively transferred NK cells with monoclonal antibody will not only result in a more potent therapeutic approach for poor- prognosis NB patients, but will be broadly applicable to other cancer populations such as lymphoma and breast carcinoma currently treated with monoclonal antibodies.

项目摘要/摘要 神经母细胞瘤（NB）是最常见的儿童颅外实体瘤。虽然密集 诱导化疗和侵略性手术的年轻患者的缓解率提高了，结果 在老年患者和40％的化学耐药性NB患者中，令人印象深刻。 诊断时> 18个月大的儿童转移性NB仅带有长期无复发生存率 〜20％。这些令人失望的结果是追求新型治疗方法的令人信服的原因。 一种替代方法是用鼠3F8进行免疫疗法，一种IgG3单克隆抗体 NB细胞上存在GD2糖抗原普遍存在。但是，它的主要缺点是 开发中和抗体，这可能会限制其有效性。 3F8管理可以授予 NB患者缓解的生存益处，但对于耐药性软组织NB的患者无效 或进行性疾病的患者。这可能部分是由于其依赖抗体的依赖性 细胞介导的细胞毒性（ADCC），后者主要由天然杀手（NK）细胞介导，它是 在经过大量预处理的患者中耗尽。 NK细胞从健康的同种异体来源转移 可以恢复并增强这些贫困风险患者的3F8效应。 天然杀手（NK）细胞是具有多个抗肿瘤活性的淋巴细胞 途径，包括通过CD16 FC受体参与的ADCC。 NK单元的容量 然而，细胞毒性反应由其细胞表面受体决定，特别是抑制性杀伤力。 像自我MHC I类分子的受体（KIR）一样。为了最大程度地发挥作用 转移的NK细胞，应该选择最大可能性的捐助者 NK同种反应性和达到最高功能性NK响应。这可以通过选择 基于供体和患者的HLA和KIR基因型的供体。 该提案提出了一种新型的免疫治疗方法，用于治疗高危 成神经细胞瘤。 3F8单克隆抗体与从属转移的NK细胞的组合 适当选择的供体应提高ADCC，抗体功效和消除肿瘤。这 高效的人源化3F8抗体的可用性可能会增加肿瘤反应 鼠类似物非常常见的中和抗体的发展。因为这些 从未对实体瘤或小儿中研究免疫方法 人口，一项I期研究，以检查人源化3F8的安全性以及不断升级的剂量 NK细胞是必要的，代表了该提案的第一个目的。 NK和3F8的潜在毒性 疗法，毒性监测计划，剂量升级计划，预期结果和停止规则是 提出。第二个目的旨在将供体 - 重视KIR/HLA免疫遗传学和供体FCR相关联 具有（1）NK激活和细胞毒性功能对NB靶细胞的多态性，（2）与（2） 患者对治疗的反应。证明安全性和可行性的相结合 具有单克隆抗体的NK细胞不仅会导致更有效的治疗方法 预后NB患者，但将广泛适用于其他癌症种群，例如淋巴瘤和 目前用单克隆抗体治疗的乳腺癌。