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: 10543552
• 负责人: Zachary Conrad Hartman
• 金额: $ 51.68万
• 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/10543552
• 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; Macrophage; Malignant Neoplasms; Mediating; Mediator; 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; cancer type; effector T cell; immune cell checkpoints; immune checkpoint blockade; improved; in vivo; innate immune checkpoint; innovation; insight; malignant breast neoplasm; neoantigens; patient response; patient subsets; polyclonal antibody; prevent; programmed cell death protein 1; recruit; resistance gene; response; standard of care; synergism; trafficking; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; vaccine strategy; 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; Macrophage; Malignant Neoplasms; Mediating; Mediator; 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; cancer type; effector T cell; immune cell checkpoints; immune checkpoint blockade; improved; in vivo; innate immune checkpoint; innovation; insight; malignant breast neoplasm; neoantigens; patient response; patient subsets; polyclonal antibody; prevent; programmed cell death protein 1; recruit; resistance gene; response; standard of care; synergism; 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.

抽象的 虽然免疫切除点封锁（ICB）已成为多种癌症中经过验证的治疗轴，但 最初的单一疗法策略仅对一部分患者有益。这些研究有 提出了T细胞在响应式癌症中的重要性，从而改善T细胞刺激和 浸润已被优先考虑。但是，我们最近的研究（Shuptrine等，2017）已经确定了 CD47/SIRPα先天途径，该途径控制抗体依赖性细胞吞噬作用（ADCP），是其中之一 抗肿瘤免疫的最关键潜在介体。这表明互补的先天反肿瘤 涉及抗体的效应子途径，特别是与ADCP有关的抗体，可能代表 建立有效的抗肿瘤反应。使用CD47先天研究的第一项临床研究的最新积极结果 ICB（耐药性淋巴瘤中的CD20 mAb）强烈表明，这可能是临床上有效的手段 刺激癌症的免疫力（Advani，NEJM，2018年）。最好在HER2+的固体癌症中探索这一点 乳腺癌（BC），目前使用HER2 MAB进行处理，我们最近确定了功能 通过ADCP（Tsao等人，JCI-Inge，在评论中）。此外，我们最近还发表了积极 来自针对HER2的疫苗策略的反应，记录诱导多克隆抗体（PABS） 在HER2+ BC患者中（Crosby等，CCR 2019）。现在，我们已经确定了这些HER2 pabs，以引起反 - 通过激活完成肿瘤的影响，允许我们研究PAB（与单克隆形成鲜明对比 HER2-ABS）可能会影响肿瘤免疫史。根据我们最近的自适应ICB机械研究 （Crosby等人，2018年），我们的中心假设是，靶向Her2靶向的mAb或PABS会依赖于抗体 吞噬作用（ADCP）通过CD47封锁对免疫学增强，以募集和主要效应子T- 可以通过使用CTLA4自适应ICB mABS扩展的单元格，并在功能上增强 使用PD1 ICB mabs。在我们的初步数据的指导下，该假设将通过使用我们的独特 HER2+ BC模型可以通过以下组合来审问，以完成我们的特定目的：1） HER2 + CD47 mAb 2）HER2/CD47 mAbs + CTLA4/PD1 ICB组合和3）HER2疫苗接种 +先天 CD47 ICB和CTLA4/PD1自适应ICB组合。这些研究将是第一个确定这些研究的方法 先天和适应性的ICB组合会影响AB介导的抗肿瘤免疫学，并机械改变 肿瘤特异性和非特异性自适应反应，并确定HER2 PAB的激活方式 补体和直接的T细胞刺激可以改变内源性HER2免疫中的抗肿瘤免疫力 具有很少的neoepitopes且具有αPD1抗性的合格模型。拟议的研究很重要， 因为如果以最小的毒性确定基本机制和协同作用，则这些方法 可以在其他固体癌症中用靶向mAb和疫苗来利用，以扩展和增强潜力 免疫疗法作为大多数癌症的治疗选择。