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: 9886858
• 负责人: Zachary Conrad Hartman
• 金额: $ 41.41万
• 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/9886858
• 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; 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

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.

抽象的 虽然免疫检查点阻断 (ICB) 已成为多种癌症的有效治疗轴， 这些研究证明，最初的单一治疗策略仅对一部分患者有益。 表明 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 然而，我们最近的研究（Shuptrine 等，2017）已经确定了渗透。 CD47/SIRPα 先天通路，控制抗体依赖性细胞吞噬作用 (ADCP)，作为 抗肿瘤免疫最关键的潜在介质，这表明互补的先天抗肿瘤作用。 涉及抗体的效应途径，特别是与 ADCP 相关的抗体，可能代表了关键途径 使用 CD47 固有的第一项临床研究最近取得了积极的结果。 ICB（在耐药性淋巴瘤中使用 CD20 mAb）强烈表明这可能是一种临床有效的方法 刺激癌症的免疫力（Advani，NEJM，2018）这可能在 HER2+ 实体癌中得到最好的探索。 乳腺癌 (BC)，目前使用我们最近确定功能的 HER2 单克隆抗体进行治疗 通过 ADCP（Tsao 等人，JCI-Insight，评论中）此外，我们最近还发布了积极的结果。 针对 HER2 的疫苗策略的反应，记录多克隆抗体 (pAb) 的诱导 在 HER2+ BC 患者中（Crosby 等人，CCR 2019），我们现在已经鉴定出这些 HER2 pAb 可引发抗- 通过激活补体来影响肿瘤，使我们能够研究 pAb（与单克隆抗体相比）如何 根据我们最近的适应性 ICB 机制研究，HER2-Abs）可能会对肿瘤免疫产生不同的影响。 (Crosby et al., 2018)，我们的中心假设是 HER2 靶向的 mAb 或 pAb 会引发抗体依赖性 CD47 阻断可增强吞噬作用 (ADCP)，从而在免疫学上招募和启动效应 T- 可以通过使用 CTLA4 适应性 ICB mAb 来扩增细胞，并通过 在我们的初步数据的指导下，我们将利用我们独特的方法来检验这一假设。 HER2+ BC 模型可以通过以下组合进行询问，这些组合构成了我们的具体目标：1) HER2+CD47 mAb 2) HER2/CD47 mAb + CTLA4/PD1 ICB 组合和 3) HER2 疫苗接种 + 先天性 CD47 ICB 和 CTLA4/PD1 适应性 ICB 组合将首次确定这些组合。 先天性和适应性 ICB 组合影响 Ab 介导的抗肿瘤免疫并机械地改变 肿瘤特异性和非特异性适应性反应，以及确定 HER2 pAb 如何激活 补体和直接 T 细胞刺激可以改变内源性 HER2 免疫中的抗肿瘤免疫 具有很少新表位并且具有 αPD1 抗性的主管模型所提出的研究意义重大， 因为如果基本机制和协同作用被确定为具有最小的毒性，那么这些方法 可以与其他实体癌的靶向单克隆抗体和疫苗一起使用，以扩大和增强潜力 免疫疗法作为大多数癌症的治疗选择的效用。