Enhancing Antibody-directed Innate Immunity to Improve Cancer Outcome

增强抗体导向的先天免疫以改善癌症结果

• 批准号: 9116791
• 负责人: PAUL M SONDEL
• 金额: $ 91.76万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116791
• 关键词: Adverse effects; Antibodies; CD94 Antigen; Cancer Patient; Cells; Child; Childhood; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Dependence; Enhancing Antibodies; Evaluation; Future; Genetic; Genotype; Goals; Guidelines; Health; Immune; Immune system; Immunity; Immunotherapy; In Vitro; Life; Ligands; Long-Term Effects; Malignant Neoplasms; Modality; Monoclonal Antibodies; Monoclonal Antibody Therapy; Morbidity - disease rate; Mus; Natural Immunity; Natural Killer Cells; Neoplasm Metastasis; Neuroblastoma; Outcome; Patients; Primary Neoplasm; Recurrence; Regimen; Sampling; Serum; Structure; Survivors; T cell response; Testing; Therapeutic Monoclonal Antibodies; Treatment Efficacy; Tumor Escape; Vision; adaptive immunity; antibody-dependent cell cytotoxicity; base; cancer therapy; cytotoxic; effective therapy; genetic analysis; improved; in vivo; macrophage; mortality; mouse model; neoplastic cell; next generation; prevent; response; selective expression; standard of care; tumor

 DESCRIPTION (provided by applicant): Despite dramatic progress, too many patients still die of cancer. Survivors often suffer from the short and long-term effects of cytotoxic/genotoxic treatments. My vision is that future cancer treatments will combine approaches that destroy cancers by intelligent focusing of the patient's own immune system, with less dependence on toxic modalities. Immunotherapy (ImmRx) is being increasingly integrated into cancer treatment, with many examples of benefit. As clinically evident cancer has escaped from a patient's immune system, effective treatment should provide the immune system with the ability to recognize a tumor it previously ignored. This can be achieved by the use of monoclonal antibody (mAb)-based agents that recognize structures selectively expressed on tumors cells. My team has made substantial contributions to basic, translational and clinical cancer ImmRx. We demonstrated that anti-tumor mAbs use endogenous innate immune cells (mainly NK cells) to initiate tumor selective antibody dependent cell-mediated cytotoxicity (ADCC) in vitro and tumor destruction in vivo. Simultaneous activation of cells responsible for ADCC synergizes with antitumor mAb-therapy. In the clinical trials we led, combinations of tumor-reactive mAbs and innate-immune activators were clinically active and are now the "standard of care" for pediatric neuroblastoma (NBL). Our analyses of patients' samples revealed how immune networks are activated, and how they may influence treatment efficacy. For example, we showed how these combination treatments can promote ADCC. Recently, using serum samples from a NBL trial, we identified an antibody in some patients, prior to any mAb treatment, directed against the therapeutic mAb. This endogenous antibody was associated with better clinical outcome. We are pursuing this finding, as it may provide ways to positively impact mAb therapy. In our mouse models, initial tumor destruction via innate immune ADCC induced a subsequent adaptive T cell response; addition of checkpoint blockade further augmented the adaptive response resulting in eradication of advanced murine tumors. Additional mouse studies led to the hypothesis that tumors escape ADCC by turning off NK cells through inhibitory NK receptors. This hypothesis was tested in patients receiving mAb (to induce ADCC). We found that patients with "favorable" NK receptor/ligand genotypes have better outcomes. The combinatory approach we are now pursuing involves mAb-directed activation of innate (NK and macrophages) immunity, induction of adaptive immunity, use of "next generation" mAb-based agents, and incorporation of genetic analyses of responsible NK receptors and their ligands. This strategy builds on the findings, momentum, and strengths of my team and our collaborations. We will systematically test, integrate and develop these concepts. Our goal is to develop life saving regimens that combine "off the shelf" agents and genetic evaluation to decrease the morbidity and mortality of cancer worldwide.

 描述（由申请人提供）：尽管取得了显着的进展，但仍有太多的患者死于癌症，幸存者经常遭受细胞毒性/基因毒性治疗的短期和长期影响。免疫疗法 (ImmRx) 越来越多地整合到患者自身的免疫系统中，从而减少对毒性疗法的依赖，并有许多临床上明显的癌症治愈案例。患者的免疫系统，有效的治疗应该使免疫系统能够识别以前忽略的肿瘤，这可以通过使用基于单克隆抗体（mAb）的药物来识别肿瘤细胞上选择性表达的结构来实现。 ImmRx 对基础、转化和临床癌症做出了重大贡献，我们证明抗肿瘤单克隆抗体利用内源性先天免疫细胞（主要是 NK 细胞）在体外启动肿瘤选择性抗体依赖性细胞介导的细胞毒性（ADCC）和肿瘤破坏。在我们领导的临床试验中，负责 ADCC 的细胞的同时激活与抗肿瘤单克隆抗体疗法具有协同作用，肿瘤反应性单克隆抗体和先天免疫激活剂的组合在临床上具有活性，并且现在是儿科神经母细胞瘤的“治疗标准”。 (NBL)。我们对患者样本的分析揭示了免疫网络如何被激活，以及它们如何影响治疗效果，例如，我们最近使用血清样本展示了这些联合治疗如何促进 ADCC。在一项 NBL 试验中，我们在任何 mAb 治疗之前在一些患者中发现了一种针对治疗性 mAb 的抗体，这种内源性抗体与更好的临床结果相关，因为它可能提供积极影响 mAb 的方法。在我们的小鼠模型中，通过先天免疫 ADCC 进行的初始肿瘤破坏诱导了随后的适应性 T 细胞反应；添加检查点阻断进一步增强了适应性反应，从而导致晚期小鼠肿瘤的根除。通过关闭NK 细胞通过抑制性 NK 受体进行了测试，我们发现具有“有利”NK 受体/配体基因型的患者具有更好的结果，其中涉及 mAb 定向激活。该策略建立了先天（NK 和巨噬细胞）免疫、诱导适应性免疫、使用“下一代”mAb 药物以及结合负责的 NK 受体及其配体的遗传分析。我们将根据我的团队的发现、动力和优势以及我们的合作，系统地测试、整合和开发这些概念，我们的目标是开发结合“现成”药物和基因评估的救生方案，以降低发病率和治疗效果。全球癌症死亡率。