Combination immunotherapy for neuroblastoma: model of innate tumor immunity

神经母细胞瘤的联合免疫治疗：先天肿瘤免疫模型

• 批准号: 8508896
• 负责人: KATHARINE C HSU
• 金额: $ 34.4万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508896
• 关键词: Activities of Daily Living; Adoptive Transfer; Age-Months; Algorithms; Allogenic; Antibodies; Antibody Therapy; Antigens; Breast Carcinoma; Cell Line; Cell Surface Receptors; Cell Therapy; Cells; Child; Childhood; Childhood Solid Neoplasm; Clinical Research; Combination Drug Therapy; Combined Modality Therapy; Dependence; Diagnosis; Disease; Disease remission; Donor Selection; Dose; Environment; FCGR3B gene; Fc Receptor; Future; Genetic Polymorphism; Genotype; Glycolipids; Histocompatibility Antigens Class I; IgG3; Immune system; Immunogenetics; Immunoglobulin G; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Inflammatory; Lead; Left; Licensing; Ligands; Lymphocyte; Lymphoma; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Memorial Sloan-Kettering Cancer Center; Modeling; Monitor; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Natural Killer Cells; Neuroblastoma; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Phase I Clinical Trials; Physicians; Population; Progressive Disease; Relapse; Resistance; Risk; Safety; Sampling; Selection Criteria; Serum; Solid Neoplasm; Source; System; Therapeutic; Time; Tissues; Toxic effect; Tumor Immunity; Up-Regulation; antibody-dependent cell cytotoxicity; base; chemotherapy; cytokine; cytotoxic; design; high risk; improved; in vivo; innovation; killings; monoclonal antibody 3F8; neuroblastoma cell; novel; novel therapeutic intervention; older patient; outcome forecast; patient population; phase 1 study; prognostic; receptor; response; soft tissue; tumor; tumor eradication

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 chemo resistant 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 successful 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 resistantsoft 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 cell 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 sel-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 and by evaluating NK function using an in vitro system that may reflect the tumor MHC environment in vivo. In the first aim of the proposal, we propose that up regulation of MHC class I molecules on the tumor selectively inhibits normally responsive NK populations, leaving the normally hypofunctional, "unlicensed" NK population to mediate ADCC in patients. Inflammatory cytokines elaborated during antibody therapy may also enhance unlicensed NK activity. The activity of the unlicensed NK population can be significant and should be considered when selecting an NK donor for adoptive transfer. This proposal presents a novel 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 I study to examine the safety of 3F8 combined with escalating doses of NK cells is necessary and represents the second 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. Donor-recipient KIR/HLA immunogenetics and donor FcR polymorphism will be correlated with NK activation and cytotoxic function against NB target cells in vitro. 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. Correlating donor-recipient KIR/HLA effects with outcome will clarify donor prioritization algorithms and provide prognostic value for future NK immunotherapy studies.

描述（由申请人提供）：神经母细胞瘤（NB）是最常见的儿童颅外实体瘤。尽管强化诱导化疗和侵略性手术的年轻患者的缓解率提高了，但在老年患者中和40％的耐化学抗性NB患者中，结果较不那么令人印象深刻。诊断时> 18个月大的儿童转移性NB的长期无复发生存率仅约为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。一种成功的替代方法是对3F8的免疫疗法，即对NB细胞上普遍存在的GD2糖抗原抗原的鼠IgG3单克隆抗体。尽管3F8给药赋予了NB患者的缓解效果明显的生存益处，但对于耐药组织NB或进行性疾病的患者而言，它无效。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），后者主要由天然杀伤（NK）细胞介导，这些细胞（NK）细胞耗尽在经过预先治疗的患者中。 NK细胞从健康的同种异体来源中传递的转移可能会恢复并增强这些贫困风险患者的3F8效应。 天然杀伤（NK）细胞是通过多种途径（包括通过CD16 FC受体参与）在内的抗肿瘤活性的淋巴细胞。但是，NK细胞对细胞毒性反应的能力取决于其细胞表面受体，特别是对SEL-MHC I类分子特有的抑制性和激活的杀伤类受体（KIR）。为了最大程度地提高经过转移的NK细胞的影响，应该选择最大程度地引起NK同种异体反应性并实现最高功能NK响应的捐助者。这可以通过根据供体和患者的HLA和KIR基因型选择供体来完成，并使用可能反映VIVO肿瘤MHC环境的体外系统评估NK功能。在该提案的第一个目的中，我们提出，在肿瘤上加强MHC I类分子的调节通常会抑制通常反应迅速的NK种群，从而使正常功能低功能，“无限制” NK NK种群介导患者的ADCC。在抗体治疗期间阐述的炎性细胞因子也可能增强无牌NK活性。无执照的NK人群的活性可能很重要，在选择NK供体进行收养转移时应考虑。 该提案为治疗高危神经母细胞瘤的新型免疫治疗方法提供了新的。 3F8单克隆抗体与从适当选择的供体转移的NK细胞的组合应提高ADCC，抗体功效和消除肿瘤。由于这些免疫方法从未研究过实体瘤或小儿种群的组合，因此必须进行I阶段的研究，以检查3F8与NK细胞不断升级的3F8的安全性，这是该提案的第二个目标。提出了NK和3F8疗法的潜在毒性，毒性监测计划，剂量升级计划，预期结果和停止规则。供体 - 恢复的KIR/HLA免疫遗传学和供体FCR多态性将与NK激活和对NB靶细胞的NK激活和细胞毒性功能相关。证明安全性和可行性 将采用的NK细胞与单克隆抗体结合起来，不仅会导致对不良预知NB患者采用更有效的治疗方法，而且将广泛适用于目前用单克隆抗体治疗的其他癌症种群，例如淋巴瘤和乳腺癌。将供体 - 培训KIR/HLA效应与结果相关联，将阐明供体优先算法算法，并为未来的NK免疫疗法研究提供预后价值。