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

基本信息

批准号：
9315788
负责人：
PAUL M SONDEL
金额：
$ 91.72万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/9315788
关键词：
Adverse effects Antibodies CD94 Antigen Cancer Patient Cells Child Childhood Clinical Clinical Treatment Clinical Trials Collaborations Dependence Evaluation Future Genetic Genotype Goals Guidelines 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 Savings Serum Structure Survivors T cell response Testing Therapeutic Monoclonal Antibodies Treatment Efficacy Tumor Escape Tumor Initiators 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 standard of care tumor

Adverse effects Antibodies CD94 Antigen Cancer Patient Cells Child Childhood Clinical Clinical Treatment Clinical Trials Collaborations Dependence Evaluation Future Genetic Genotype Goals Guidelines 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 Savings Serum Structure Survivors T cell response Testing Therapeutic Monoclonal Antibodies Treatment Efficacy Tumor Escape Tumor Initiators 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 standard of care tumor

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项目摘要

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（由适用提供）：尽管进展很大，但太多的患者仍然死于癌症。幸存者经常遭受细胞毒性/遗传毒性治疗的短期和长期影响。我的愿景是，未来的癌症治疗方法将结合通过智能关注患者自己的免疫系统来破坏癌症的方法，而对毒性方式的依赖较小。免疫疗法（IMMRX）越来越多地纳入癌症治疗，并有许多益处的例子。由于临床证据癌症已经从患者的免疫系统中逃脱了，因此有效的治疗应为免疫系统提供识别先前忽略的肿瘤的能力。这可以通过使用单克隆抗体（MAB）的药物来实现，这些抗体（MAB）的药物在肿瘤细胞上有选择地表达结构。我的团队为基本，翻译和临床癌症IMMRX做出了重大贡献。我们证明，抗肿瘤mAb在体外和肿瘤破坏体内使用内源性先天免疫小球（主要是NK细胞）来启动肿瘤选择性抗体选择性抗体的细胞介导的细胞毒性（ADCC）。同时激活负责ADCC的细胞与抗肿瘤mab-疗法协同作用。在我们领导的临床试验中，肿瘤反应性mAB和先天免疫活化剂的组合具有临床活性，现在是小儿神经母细胞瘤（NBL）的“护理标准”。我们对患者样本的分析揭示了免疫网络如何激活，以及它们如何影响治疗效率。例如，我们展示了这些组合治疗方法如何促进ADCC。最近，使用来自NBL试验的血清样品，我们在针对治疗性mAb的任何MAB治疗之前鉴定了某些患者中的一种抗体。该内源性抗体与更好的临床结局有关。我们正在追求这一发现，因为它可能会提供积极影响mAB疗法的方法。在我们的小鼠模型中，通过先天免疫ADCC的初始肿瘤破坏会引起随后的自适应T细胞反应。添加检查点阻滞进一步增强了自适应反应，导致了晚期鼠肿瘤的消灭。其他小鼠的研究导致了以下假设：肿瘤通过通过抑制性NK受体关闭NK细胞来逃脱ADCC。该假设在接受MAB的患者中进行了检验（诱导ADCC）。我们发现，具有“有利” NK受体/配体基因型的患者的预后更好。我们现在采用的组合方法涉及MAB定向的先天性（NK和巨噬细胞）免疫组织化学，适应性免疫学的诱导，使用“下一代” MAB基于MAB的药物，并结合了负责任的NK受体及其配体的基因分析。这种策略以我团队和我们的合作的发现，动力和优势为基础。我们将系统地测试，集成并开发这些概念。我们的目标是开发挽救生命的方案，该方案结合了“货架”代理和遗传评估，以降低全球癌症的发病率和死亡率。