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。虽然密集的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%的化疗耐药的NB患者中，结果并不令人印象深刻。一种替代方法是用3F8进行免疫治疗，3F8是一种针对GD2糖脂抗原的小鼠IgG3单抗，普遍存在于NB细胞中。虽然3F8给药对缓解期的NB患者有明显的生存益处，但对软组织耐药的NB患者或进展性疾病患者无效。这可能部分是因为它依赖于抗体依赖的细胞介导的细胞毒作用(ADCC)，后者主要由自然杀伤(NK)细胞介导，而严重预治疗的患者会耗尽自然杀伤细胞(NK细胞)。从健康的同种异体来源过继转移NK细胞可能会恢复和增强这些低风险患者的3F8效应。自然杀伤(NK)细胞是通过多种途径具有抗肿瘤活性的淋巴细胞，包括通过与CD16Fc受体结合的ADCC。然而，NK细胞对细胞毒反应的能力是由其细胞表面受体决定的，特别是针对自身MHC(主要组织相容性)I类分子的抑制性和激活性KIR。为了最大限度地发挥过继转移的NK细胞的作用，应该选择最有可能产生NK同种异体反应和获得最高功能NK反应的供者。这可以通过根据捐赠者和患者的人类白细胞抗原和KIR基因类型选择捐赠者来实现。这项建议提出了一种治疗高危神经母细胞瘤的免疫治疗方法。3F8单抗与来自适当选择的供者的过继转移的NK细胞相结合，将增加ADCC、抗体效力和肿瘤根除。由于这些免疫学方法从未在实体肿瘤或儿科人群中进行联合研究，因此有必要进行一项第一阶段研究，以检查3F8联合不断增加的NK细胞剂量的安全性，这是该提案的第一个目标。介绍了NK和3F8治疗的潜在毒性、毒性监测计划、剂量递增计划、预期结果和停药规则。第二个目的是寻找供体-受体KIR/HLA免疫遗传学和供体FCR基因多态性与(1)NK细胞体外对NB靶细胞的激活和细胞毒作用，以及(2)患者对治疗的反应之间的关系。

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.