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: 10001324
• 负责人: PAUL M SONDEL
• 金额: $ 91.37万
• 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/10001324
• 关键词: Antibodies; Antibody Therapy; CD94 Antigen; Cancer Patient; Cells; Child; Childhood; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Combination immunotherapy; Dependence; Evaluation; Future; Genetic; Genotype; Goals; Guidelines; Immune; Immune system; Immunity; Immunotherapy; In Vitro; Intelligence; 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; Savings; Serum; Structure; Survivors; T cell response; Testing; Therapeutic Monoclonal Antibodies; Treatment Efficacy; Tumor Escape; Vision; adaptive immunity; antibody-dependent cell cytotoxicity; base; cancer immunotherapy; cancer therapy; cytotoxic; effective therapy; genetic analysis; genotoxicity; immune checkpoint blockade; improved; in vivo; macrophage; mortality; mouse model; neoplastic cell; next generation; prevent; public health relevance; response; selective expression; side effect; 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(申请人提供)：尽管取得了巨大的进步，但仍有太多的患者死于癌症。幸存者往往遭受细胞毒性/基因毒性治疗的短期和长期影响。我的愿景是，未来的癌症治疗将结合通过智能聚焦患者自身的免疫系统来摧毁癌症的方法，而不是更少地依赖有毒方式。免疫疗法(ImmRx)正越来越多地被整合到癌症治疗中，有许多有益的例子。由于临床上癌症已经从患者的免疫系统中逃脱，有效的治疗应该为免疫系统提供识别以前被忽视的肿瘤的能力。这可以通过使用基于单抗(MAb)的试剂来实现，这些试剂识别肿瘤细胞上选择性表达的结构。我的团队在基础、转化性和临床癌症ImmRx方面做出了实质性贡献。我们证明了抗肿瘤单抗在体外利用内源性天然免疫细胞(主要是NK细胞)启动肿瘤选择性抗体依赖的细胞介导的细胞毒作用(ADCC)和体内的肿瘤杀伤作用。负责ADCC的细胞的同时激活与抗肿瘤单抗治疗有协同作用。在我们领导的临床试验中，肿瘤反应性单抗和天然免疫激活剂的组合在临床上是有效的，现在是儿童神经母细胞瘤(NBL)的“标准治疗”。我们对患者样本的分析揭示了免疫网络是如何激活的，以及它们可能如何影响治疗效果。例如，我们展示了这些联合治疗如何促进ADCC。最近，使用NBL试验的血清样本，我们在一些患者中发现了一种抗体，在任何mAb治疗之前，针对治疗性mAb。这种内源性抗体与更好的临床结果相关。我们正在追寻这一发现，因为它可能提供积极影响单抗治疗的方法。在我们的小鼠模型中，通过先天免疫ADCC最初的肿瘤破坏诱导了随后的适应性T细胞反应；增加检查点阻断进一步增强了适应性反应，导致晚期小鼠肿瘤的根除。另外的小鼠研究导致了一种假设，即肿瘤通过抑制NK受体关闭NK细胞来逃避ADCC。这一假设在接受单抗(以诱导ADCC)的患者中得到验证。我们发现，具有“良好”NK受体/配体基因型的患者预后较好。我们现在追求的组合方法包括mAb引导的天然(NK和巨噬细胞)免疫的激活，适应性免疫的诱导，基于mAb的“下一代”制剂的使用，以及对负责任的NK受体及其配体的遗传分析。这一战略建立在我的团队和我们的合作成果、势头和优势的基础上。我们将系统地测试、整合和发展这些理念。我们的目标是开发结合“现成”制剂和基因评估的救命方案，以降低全球癌症的发病率和死亡率。