Phase 1 Study of Immunotherapy with NK Cells anti-GD2 for Neuroblastoma

描述（由申请人提供）： 神经母细胞瘤（NB）是儿童最常见的颅外实体瘤。虽然强化诱导化疗和积极的手术提高了年轻患者的缓解率，但在老年患者和40%的化疗耐药NB患者中，结果并不令人印象深刻。一种替代方法是用3F 8免疫治疗，3F 8是一种针对NB细胞上普遍存在的GD 2糖脂抗原的鼠IgG 3单克隆抗体。虽然3F 8给药对缓解期NB患者具有明显的生存益处，但对耐药软组织NB患者或进行性疾病患者无效。这可能部分是由于其依赖于抗体依赖性细胞介导的细胞毒性（ADCC），后者主要是由自然杀伤（NK）细胞介导的，在大量预治疗的患者中被耗尽。从健康的同种异体来源连续转移NK细胞可能会恢复和增强这些低风险患者的3F 8效应。自然杀伤（NK）细胞是具有通过多种途径（包括通过与CD 16 Fc受体结合的ADCC）发挥抗肿瘤活性的能力的淋巴细胞。然而，NK细胞的细胞毒性应答能力由其细胞表面受体决定，特别是对自身MHC（主要组织相容性）I类分子特异的抑制性和活化性免疫球蛋白样受体（KIR）。为了最大限度地发挥过继转移NK细胞的作用，应该选择最有可能产生NK同种异体反应性并实现最高功能性NK反应的供体。这可以通过基于供体和患者的HLA和KIR基因型选择供体来实现。该提案提出了一种用于治疗高危神经母细胞瘤的免疫方法。3F 8单克隆抗体与从适当选择的供体过继转移的NK细胞的组合应增加ADCC、抗体效力和肿瘤根除。由于这些免疫学方法从未在实体瘤或儿科人群中进行过联合研究，因此有必要进行1期研究，以检查3F 8与递增剂量的NK细胞联合使用的安全性，这是该提案的首要目标。介绍了NK和3F 8治疗的潜在毒性、毒性监测计划、剂量递增计划、预期结局和停止规则。第二个目的是寻求将供体-受体KIR/HLA免疫遗传学和供体FcR多态性与（1）体外NK活化和针对NB靶细胞的细胞毒性功能以及（2）患者对治疗的反应相关联。

DESCRIPTION (provided by applicant): 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. One alternative approach has been immunotherapy with 3F8, a murine IgG3 monoclonal antibody to the GD2 glycolipid antigen ubiquitously present on NB cells. While 3F8 administration confers a clear survival benefit to NB patients in remission, 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 may 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 and activating killer-Ig like receptors (KIR) that are specific for self-MHC (major histocompatibility) 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 an immunotherapeutic approach for the treatment of high-risk neuroblastoma. Combination of 3F8 monoclonal antibody with adoptively transferred NK cells from appropriately selected donors should increase ADCC, antibody efficacy, and tumor eradication. Because these immunologic approaches have never been studied in combination for a solid tumor or in the pediatric population, a Phase 1 study to examine the safety of 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.