Enhancing Antibody-directed Innate Immunity to Improve Cancer Outcome

 描述（由申请人提供）：尽管取得了巨大进展，但仍有太多患者死于癌症。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。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免疫系统来消灭癌症​​的方法，同时减少对毒性方式的依赖。免疫疗法 (ImmRx) 越来越多地融入癌症治疗，并有许多益处的例子。由于临床上明显的癌症已经从患者的免疫系统中逃脱，有效的治疗应该使免疫系统能够识别以前被忽视的肿瘤。这可以通过使用基于单克隆抗体 (mAb) 的试剂来实现，这些试剂可识别肿瘤细胞上选择性表达的结构。我的团队对基础、转化和临床癌症 ImmRx 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），并在体内启动肿瘤破坏。同时激活负责 ADCC 的细胞与抗肿瘤单克隆抗体疗法具有协同作用。在我们领导的临床试验中，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，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是如何激活的，以及它们如何影响治疗效果。例如，我们展示了这些联合治疗如何促进 ADCC。 最近，我们利用 NBL 试验的血清样本，在进行任何 mAb 治疗之前，在一些患者体内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。我们正在研究这一发现，因为它可能提供对单克隆抗体治疗产生积极影响的方法。 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；添加检查点封锁进一步增强了适应性反应，从而根除晚期小鼠肿瘤。其他小鼠研究得出这样的假设：肿瘤通过抑制性 NK 受体关闭 NK 细胞来逃避 ADCC。这一假设在接受 mAb（以诱导 ADCC）的患者中得到了检验。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。 我们现在追求的组合方法涉及 mAb 定向激活先天（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。该战略建立在我的团队以及我们的合作的发现、动力和优势之上。我们将系统地测试、整合和发展这些概念。我们的目标是开发结合“现成”药物和基因评估的挽救生命的方案，以降低全世界癌症的发病率和死亡率。

 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.