Enabling effective anti-tumor immunity from targeted antibodies through dual innate and adaptive immune checkpoint blockade in non-immunogenic cancers

通过先天性和适应性免疫检查点双重阻断非免疫原性癌症，实现靶向抗体的有效抗肿瘤免疫

• 批准号: 10271164
• 负责人: Zachary Conrad Hartman
• 金额: $ 8.56万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-06 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10271164
• 关键词: Address; Affect; Antibodies; Antibody Therapy; Antitumor Response; Binding; CD47 gene; CD47-SIRPα; CTLA4 gene; Cells; Clinical; Clinical Research; Clone Cells; Cross Presentation; Cross-Priming; Data; Development; ERBB2 gene; Epitopes; Extracellular Domain; Funding; Health; Heterogeneity; Human; Immune; Immune Tolerance; Immune response; Immunity; Immunotherapy; Infiltration; Knowledge; Malignant Neoplasms; Mediating; Mission; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Nature; Oncogenic; Oncology; PD-1/PD-L1; Pathologic; Pathology; Pathway interactions; Patients; Protein Isoforms; Public Health; Research; Resistance; Resistance development; T cell response; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Trastuzumab; Tumor Immunity; Tumor-infiltrating immune cells; United States National Institutes of Health; Vaccines; Variant; anti-PD-1; anti-tumor immune response; antibody immunotherapy; antibody-dependent cellular phagocytosis; extracellular; immune checkpoint blockade; improved; innate immune checkpoint; innovation; insight; mammary; molecular subtypes; novel; patient subsets; polyclonal antibody; prevent; programmed cell death protein 1; programs; resistance mechanism; standard of care; stem; therapeutic development; therapy resistant; tumor; tumor heterogeneity

Abstract In our previous studies, we have identified that HER2 monoclonal antibodies (mAb) function to stimulate antibody dependent cellular phagocytosis (ADCP) through innate pathways, which are critical to establish effective anti-tumor responses (Tsao et al., JCI-Insight, 2019). In our ongoing funded studies (R01 CA238217- 01A1), we are exploring if HER2-specific ADCP eliciting antibodies could be enhanced by innate ICB (targeting CD47) and adaptive ICBs (targeting CTLA4/PD1). These studies utilize an endogenous immune-tolerant model of HER2+ BC (Turpin et al., 2016) driven by an oncogenic human isoform of HER2, HER2Δ16. While this model is immune-tolerant to HER2 epitopes and generates HER2Δ16-driven tumors in an appropriate mammary microenvironment, it does not recapitulate the tumor heterogeneity seen clinically in HER2+ BCs, or permit the development of major resistance mechanisms to HER2 mAb therapies, which often occur in advanced HER2+ BC patients. To address these shortcomings and further our understanding of HER2 mAb therapies in HER2+ BC, we propose to utilize a novel HER2BOW mouse developed through the IMAT program (5R33CA191198;Lubkov et al., Nat. Cell Bio., in review). This model utilizes the stochastic activation of several different variants of HER2 (HER2-WT, HER2Δ16, and HER2-p95) within the mammary compartment to evolve heterogeneous HER2+ BCs with disparate pathologies. Critically, these different pathologies stem from the expression of these alternate HER2 isoforms, which may explain HER2+ tumor heterogeneity observed clinically. Moreover, this model contains HER2-p95, which lacks the extracellular binding domain for HER2 mAbs to function as a driver of resistance. However, HER2-specific mAbs are able to prime T cell responses against HER2 intracellular epitopes within the heterogeneous context of clinical HER2+ BCs, thus its importance in mediating resistance in a heterogeneous context is unclear. Moreover, it is unknown if strategies to enhance HER2 mAb stimulated immunity could overcome HER2-p95 mediated resistance thorough enhanced HER2 immune cross-priming. We hypothesize that HER2-p95 expression confers resistance against HER2 mAb therapies within heterogeneous HER2+ BCs, but that dual (innate and adaptive) ICB-enhanced HER2 mAb therapies could overcome this resistance through enhance HER2 epitope cross-priming. Guided by our preliminary data, this hypothesis will be tested by utilizing the HER2BOW model that can be interrogated with the following combinations that comprise our specific aims: 1) HER2+CD47 mAbs and 2) HER2/CD47 mAbs + CTLA4/PD1 ICB combinations. These studies will determine if responsiveness is due to a lack of local immunity related to substantial intratumoral heterogeneity, or due to the rapid development of resistance from alternate HER2 oncogenic isoforms. Critically, they will also validate the therapeutic utility of the HER2BOW model and the therapeutic potential of HER2 mAb+ICB combinations across different HER2+ BCs as well as their impact on the development of HER2 mAb mediated resistance.

摘要 在我们以前的研究中，我们已经确定了HER 2单克隆抗体（mAb）的功能是刺激HER 2表达。 抗体依赖性细胞吞噬作用（ADCP）通过先天途径，这是建立 有效的抗肿瘤反应（Tsao等，JCI-Insight，2019）。在我们正在进行的资助研究（R 01 CA 238217- 01 A1），我们正在探索是否可以通过先天性ICB（靶向 CD 47）和适应性ICB（靶向CTLA 4/PD 1）。这些研究利用内源性免疫耐受模型 HER 2 + BC（Turpin等，2016）由HER 2的致癌人类同种型HER 2 Δ16驱动。虽然这 模型对HER 2表位具有免疫耐受性，并在适当的条件下产生HER 2 Δ16驱动的肿瘤。 乳腺微环境，不重现临床上在HER 2 + BC中观察到的肿瘤异质性，或 允许对HER 2 mAb治疗产生主要耐药机制，这通常发生在 晚期HER 2 + BC患者。为了解决这些缺点并进一步了解HER 2 mAb 在HER 2 + BC的治疗中，我们建议利用通过IMAT计划开发的新型HER 2BOW小鼠 （5 R33 CA 191198;Lubkov等人，Nat. Cell Bio.，审查中）。该模型利用了几个随机激活 乳腺隔室中的不同HER 2变体（HER 2-WT、HER 2 Δ16和HER 2-p95） 具有不同病理的异质HER 2 + BC。重要的是，这些不同的病理源于 这些替代HER 2亚型的表达，这可能解释了观察到的HER 2+肿瘤异质性 临床上此外，该模型含有HER 2-p95，其缺乏HER 2的细胞外结合结构域 单克隆抗体作为阻力的驱动器。然而，HER 2特异性mAb能够引发T细胞应答， 在临床HER 2 + BC的异质性背景下针对HER 2细胞内表位，因此其 在异质背景下介导抗性的重要性尚不清楚。此外，还不清楚战略是否 增强HER 2 mAb刺激的免疫力可以彻底克服HER 2-p95介导的耐药性， 增强的HER 2免疫交叉致敏。我们假设HER 2-p95表达赋予抗肿瘤的抗性， 异质性HER 2 + BC中的HER 2 mAb治疗，但双重（先天性和适应性）ICB增强 HER 2 mAb疗法可以通过增强HER 2表位交叉致敏来克服这种耐药性。指导 我们的初步数据，这一假设将通过使用HER 2BOW模型进行测试，可以询问 与包含我们特定目标的以下组合：1）HER 2 + CD 47 mAb和2）HER 2/CD 47 mAb + CTLA 4/PD 1 ICB组合。这些研究将确定反应是否是由于缺乏当地的 免疫相关的实质性瘤内异质性，或由于快速发展的耐药性， 交替的HER 2致癌亚型。重要的是，他们还将验证HER 2BOW的治疗效用 模型和HER 2 mAb+ICB组合在不同HER 2 + BC中的治疗潜力，以及 它们对HER 2 mAb介导的耐药性发展的影响。