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

项目摘要/摘要 神经母细胞瘤(NB)是儿童最常见的颅外实体瘤。虽然强度很大 结果显示，诱导化疗和积极手术提高了年轻患者的缓解率 在老年患者和40%的化疗耐药的NB患者中不那么令人印象深刻。 确诊时18个月大的儿童转移性神经母细胞瘤仅有长期无复发生存 ~20%。这些令人失望的结果是寻求新的治疗方法的令人信服的理由。 另一种替代方法是用小鼠3F8进行免疫治疗，3F8是一种抗人免疫球蛋白3的单抗 GD2糖脂抗原广泛存在于NB细胞上。然而，它的主要缺点是 发展中和抗体，这可能会限制其有效性。3F8管理可以授予 生存对缓解期的NB患者有利，但对软组织耐药的NB患者无效 或进展性疾病的患者。这可能部分归因于它对抗体依赖性的依赖。 细胞介导的细胞毒性(ADCC)，后者主要由自然杀伤(NK)细胞介导，后者是 在经过大量预治疗的患者中消耗殆尽。来自健康同种异体来源的NK细胞过继转移 可以恢复和增强这些低风险患者的3F8效果。 自然杀伤(NK)细胞是一种具有抗肿瘤活性的淋巴细胞，它通过 途径，包括通过参与CD16Fc受体的ADCC。自然杀伤细胞的能力 然而，细胞毒性反应是由其细胞表面受体决定的，特别是抑制性杀伤分子-Ig 类受体(KIR)是针对自身MHC I类分子的。为了最大限度地发挥收养的效果 转移的NK细胞，应该选择最有可能产生的捐赠者 NK同种异体反应性和获得最高功能的NK应答。这可以通过选择 捐赠者根据捐赠者和患者的人类白细胞抗原和KIR基因分型。 这项建议提出了一种新的免疫治疗方法，用于治疗高危疾病。 神经母细胞瘤。3F8单抗与过继转移的人外周血NK细胞的结合 选择适当的供者应增加ADCC、抗体效力和肿瘤根除。这个 获得一种高效的人源化3F8抗体可能会增加肿瘤的反应，同时避免 发展中和抗体，这种抗体在小鼠类似物中是如此常见。因为这些 免疫学方法从未对实体瘤或儿童肿瘤的联合治疗进行过研究。 人口，这是一项第一阶段的研究，旨在检查人源化3F8与不断增加的剂量联合使用的安全性 NK细胞是必要的，也是该提案的首要目标。NK和3F8的潜在毒性 治疗、毒性监测计划、剂量升级计划、预期结果和停药规则如下 呈上了。第二个目标是寻求供体-受体KIR/人类白细胞抗原免疫遗传学与供体FCR之间的关系 多态与(1)NK激活和体外对NB靶细胞的细胞毒作用，以及(2)与 患者对治疗反应。联合采用转移的安全性和可行性论证 带有单抗的NK细胞不仅将为穷人提供一种更有效的治疗方法。 预后NB患者，但将广泛适用于其他癌症人群，如淋巴瘤和 目前用单抗治疗乳腺癌。

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.