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: 10305641
• 负责人: Zachary Conrad Hartman
• 金额: $ 60.16万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305641
• 关键词: Antibodies; Antibody Response; Antibody Therapy; Antigens; Antitumor Response; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; CCR; CD47 gene; CD47-SIRPα; CTLA4 gene; Cells; Chemotherapy and/or radiation; Clinical; Clinical Pathways; Clinical Research; Clone Cells; Complement; Complement 3a; Complement 5a; Complement Activation; Critical Pathways; Data; Deposition; ERBB2 gene; Epitopes; Health; Human; Immune; Immune Tolerance; Immunity; Immunocompetent; Immunologics; Immunosuppression; Immunotherapy; Infiltration; Inflammation; Knockout Mice; Knowledge; Lymphoma; MS4A1 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Mission; Modeling; Monoclonal Antibodies; Mus; Non-Hodgkin' s Lymphoma; Oncology; Outcome; PD-1 blockade; PD-1/PD-L1; Pathway interactions; Phagocytes; Phagocytosis; Phase I Clinical Trials; Phase II Clinical Trials; Public Health; Publishing; Radiation therapy; Regulatory T-Lymphocyte; Reporting; Research; Resistance; Signal Transduction; Solid; Solid Neoplasm; T cell response; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Trastuzumab; Tumor Antigens; Tumor Immunity; United States National Institutes of Health; Vaccination; Vaccines; anti-CTLA4; anti-PD-1; anti-tumor immune response; antibody immunotherapy; antibody-dependent cellular phagocytosis; antigen-specific T cells; antitumor effect; base; cancer type; effector T cell; immune cell checkpoints; immune checkpoint blockade; improved; in vivo; innate immune checkpoint; innovation; insight; macrophage; malignant breast neoplasm; neoantigens; patient response; patient subsets; polarized cell; polyclonal antibody; prevent; programmed cell death protein 1; recruit; resistance gene; response; standard of care; synergism; therapeutic vaccine; trafficking; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; vaccine strategy

Abstract While immune checkpoint blockade (ICB) has emerged as a validated therapeutic axis in a variety of cancers, initial monotherapy strategies have proven beneficial only to a subset of patients. These studies have suggested the importance of T-cells in responsive cancers, thus strategies to improve T-cell stimulation and infiltration have been prioritized. However, our recent studies (Shuptrine et al., 2017) have identified the CD47/SIRPα innate pathway, which governs antibody dependent cell phagocytosis (ADCP), as one of the most critical potential mediators of anti-tumor immunity. This suggests that complementary innate anti-tumor effector pathways involving antibodies, particularly relating to ADCP, may represent critical pathways to establish effective anti-tumor responses. Recent positive results from the first clinical study using CD47 innate ICB (with CD20 mAb in resistant lymphoma) strongly suggest that this may be a clinically effective means to stimulate immunity in cancers (Advani, NEJM, 2018). This may be best explored in solid cancers in HER2+ Breast Cancer (BC), which are currently treated using HER2 mAbs that we recently determined function through ADCP (Tsao et al., JCI-Insight, in review). Additionally, we have also recently published positive responses from a vaccine strategy targeting HER2, documenting the induction of polyclonal antibodies (pAbs) in HER2+ BC patients (Crosby et al., CCR 2019). We have now identified these HER2 pAbs to elicit anti- tumor effects through the activation of complement, allowing our study of how pAbs (in contrast to monoclonal HER2-Abs) may differentially impact tumor immunity. Based on our recent adaptive ICB mechanistic studies, (Crosby et al., 2018), our central hypothesis is that HER2-targeted mAbs or pAbs elicit antibody dependent phagocytosis (ADCP) that is enhanced by CD47 blockade to immunologically to recruit and prime effector T- cells that can be expanded through the use of CTLA4 adaptive ICB mAbs and functionally enhanced by the use of PD1 ICB mAbs. Guided by our preliminary data, this hypothesis will be tested by utilizing our unique HER2+ BC models that can be interrogated with the following combinations that comprise our specific aims: 1) HER2+CD47 mAbs 2) HER2/CD47 mAbs + CTLA4/PD1 ICB combinations and 3) HER2 vaccination + innate CD47 ICB and CTLA4/PD1 adaptive ICB combinations. These studies will be the first to determine how these innate and adaptive ICB combinations impact Ab-mediated anti-tumor immunity and mechanistically alter tumor-specific and non-specific adaptive responses, as well as determine how the HER2 pAb activation of complement and direct T-cell stimulation can alter anti-tumor immunity in an endogenous HER2 immune- competent model that possesses few neoepitopes and is αPD1 resistant. The proposed research is significant, because if fundamental mechanisms and synergies are identified with minimal toxicities, these approaches could be utilized with targeted mAbs and vaccines in other solid cancers to expand and enhance the potential utility of immunotherapy as a therapeutic option for the majority of cancers.

摘要 虽然免疫检查点阻断（ICB）已成为各种癌症中经验证的治疗轴， 最初的单一疗法策略已被证明仅对一部分患者有益。这些研究 提出了T细胞在反应性癌症中的重要性，因此提出了改善T细胞刺激和 渗透已被优先考虑。然而，我们最近的研究（Shuptrine等人，2017年）已经确定了 CD 47/SIRPα先天性途径，其控制抗体依赖性细胞吞噬作用（ADCP），作为免疫调节剂之一。 抗肿瘤免疫的最关键的潜在介质。这表明互补的先天性抗肿瘤 涉及抗体的效应子途径，特别是与ADCP相关的效应子途径，可能是 建立有效的抗肿瘤反应。使用先天性CD 47的第一项临床研究的最新阳性结果 ICB（在耐药淋巴瘤中使用CD 20 mAb）强烈表明，这可能是一种临床有效的方法， 刺激癌症免疫（Advani，NEJM，2018）。这可能在HER 2+的实体癌中进行了最佳探索 乳腺癌（BC），目前使用HER 2 mAb治疗，我们最近确定了其功能 通过ADCP（Tsao等人，JCI-Insight，审查中）。此外，我们最近还发表了积极的 靶向HER 2的疫苗策略的应答，记录多克隆抗体（pAb）的诱导 在HER 2 + BC患者中（克罗斯比等人，CCR 2019）。我们现在已经鉴定了这些HER 2 pAb，以引起抗- 肿瘤的影响，通过激活补体，使我们的研究如何pAb（与单克隆抗体相比， HER 2-Abs）可能差异性地影响肿瘤免疫。基于我们最近的自适应ICB机制研究， （克罗斯比等人，2018），我们的中心假设是HER 2靶向mAb或pAb引起抗体依赖性 吞噬作用（ADCP），其通过CD 47阻断而增强，以在免疫学上募集和引发效应T细胞。 可以通过使用CTLA 4适应性ICB mAb扩增并通过使用CTLA 4适应性ICB mAb增强功能的细胞。 使用PD 1 ICB mAb。在我们初步数据的指导下，这一假设将通过利用我们独特的 HER 2 + BC模型，可以用包含我们特定目标的以下组合进行询问：1） 2）HER 2/CD 47 mAb + CTLA 4/PD 1 ICB组合和3）HER 2疫苗接种+先天性 CD 47 ICB和CTLA 4/PD 1适应性ICB组合。这些研究将是第一个确定这些 先天性和适应性ICB组合影响Ab介导的抗肿瘤免疫， 肿瘤特异性和非特异性适应性应答，以及确定HER 2 pAb如何激活肿瘤细胞， 补体和直接T细胞刺激可以改变内源性HER 2免疫中的抗肿瘤免疫， 具有较少新表位且对α PD 1耐药的胜任模型。拟议的研究意义重大， 因为如果以最小的毒性确定基本机制和协同作用，这些方法 可以与靶向mAb和疫苗一起用于其他实体癌，以扩大和增强 免疫疗法作为大多数癌症的治疗选择的效用。