Antibody-Targeted Cancer Immunotherapy

抗体靶向癌症免疫治疗

• 批准号: 8788503
• 负责人: Louis M. Weiner
• 金额: $ 34.71万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-06-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788503
• 关键词: ABL1 gene; Antibodies; Antibody Therapy; Antigen Presentation; Apoptosis; Biopsy; Breast Cancer Cell; Breast Cancer cell line; Cell Line; Cell Survival; Cells; Cetuximab; Clinic; Clinical; Clinical Trials; Disease; Enhancing Antibodies; Epidermal Growth Factor Receptor; Event; Family; Fc Receptor; Funding; Gene Expression; Genes; Genetic Polymorphism; Genome; Genomic approach; Genomics; Goals; Growth; Health; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunodeficient Mouse; In Vitro; Libraries; Malignant Neoplasms; Mediating; Modeling; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phosphorylation; Protein Kinase C; Protein Microchips; Proto-Oncogene Proteins c-abl; Relapse; Resistance; SCID Mice; Sampling; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Testing; Tetanus Helper Peptide; Time; Transgenic Organisms; Translating; Treatment-Associated Neoplasms; Tumor Cell Line; Tumor Immunity; Vaccination; Work; Xenograft procedure; adaptive immunity; antibody-dependent cell cytotoxicity; antitumor agent; antitumor effect; base; c-abl Proto-Oncogenes; cancer cell; cancer immunotherapy; cancer therapy; established cell line; exome sequencing; functional genomics; improved; in vivo; innovation; killings; neoplastic cell; novel; novel strategies; pressure; prevent; protein expression; screening; small hairpin RNA; therapy outcome; tumor

DESCRIPTION (provided by applicant): Our long-term goal is to improve the efficacy of EGFR family-directed monoclonal antibody therapy with the overarching hypothesis that antibodies can be combined with other anti-tumor agents to promote host- protective adaptive immunity that improves cancer therapy. In the current funding period we have 1) defined tumor cell based determinants of anti-tumor efficacy and promotion of antibody-dependent cellular cytotoxicity (ADCC) such as c-Abl and protein kinase C-¿, 2) demonstrated that effective antibody therapy promotes host-protective immune responses, and 3) employed a novel shRNA library screening strategy to identify Tex9 and other tumor cell-based determinants of immune rejection. We now propose to translate these findings into the clinic, and to develop innovative new approaches to improve antibody-initiated tumor rejection. The first aim is to define EGFR network-related signaling following therapy with cetuximab, nilotinib or the combination in a Phase I clinical tria of these drugs in patients with solid tumors. The second aim is to enhance antibody-dependent cellular cytotoxicity (ADCC) and improve its in vivo anti-tumor effects. We will test the hypotheses that 1) nilotinib therapy or protein kinase C-¿ knockdown enhance ADCC and subsequent antigen presentation, and 2) strategies to enhance ADCC promote the anti-tumor effects of cetuximab. The third aim is to identify new tumor cell-based molecular determinants of immune rejection in murine models. We have screened a barcoded murine whole-genome shRNA library in vivo and identified genes whose knockdown in EO771 breast tumor cells selectively enriches or depletes such cells in tumors in NSG, WT C57Bl/6 and SCID C57Bl/6 mice. We hypothesize that in vivo genomic screening can identify new targets that alter immune rejection initiated by monoclonal antibody therapy or vaccination. The successful execution of this work will have high impact by 1) defining the value of synthetic lethal screening to identify MAb-based combinations (Aim 1), 2) demonstrating new ways to promote ADCC-induced host protection (Aim 2), and 3) defining new targets and pathways that regulate tumor cell-based sensitivity and resistance to antibody-initiated host immunity (Aim 3). These results will have resonance for the field of tumor immunity. RELEVANCE: Monoclonal antibodies (MAb) are useful treatments for many tumor types, but new approaches are needed to improve therapy outcomes. We aim to improve the ability of MAb to directly kill cancer cells, and to stimulate the body's immune system so that people can be immunized against their cancers to prevent or delay relapse or disease worsening.

描述（由适用提供）：我们的长期目标是提高EGFR家族指导的单克隆抗体治疗的效率，并具有总体假设，即可以将抗体与其他抗肿瘤剂结合起来，以促进宿主受保护的适应性免疫学改善癌症治疗。在当前的资金期间，我们有1）定义的基于肿瘤细胞的抗肿瘤效率的决定剂，并促进抗肿瘤细胞细胞毒性（ADCC），例如C-ABL和蛋白激酶C-¿免疫反应。现在，我们建议将这些发现转化为诊所，并开发创新的新方法来改善抗体引起的肿瘤排斥。第一个目的是在用西妥昔单抗，尼洛替尼或在实体瘤患者的I阶段临床三亚临床三亚纤维中定义与EGFR网络相关的信号传导。第二个目的是增强抗体依赖性细胞毒性（ADCC）并改善其体内抗肿瘤作用。我们将检验以下假设：1）尼洛替尼治疗或蛋白激酶C-lockdown增强ADCC和随后的抗原表现，以及2）增强ADCC的策略，促进了cetuximab的抗肿瘤作用。第三个目的是鉴定鼠模型中免疫反应的新型肿瘤细胞分子决定剂。我们在体内筛选了一个条形码的鼠全基因组shRNA文库，并鉴定了其在NSG，WT C57BL/6和SCID C57BL/6小鼠中，在EO771乳腺肿瘤细胞中敲低的基因。我们假设体内基因组筛查可以鉴定出改变由单克隆抗体疗法或疫苗接种引发的免疫注射的新靶标。这项工作的成功执行将产生很大的影响1）定义合成致命筛查的价值，以识别基于mAb的组合（AIM 1），2）展示促进ADCC诱导的宿主保护的新方法（AIM 2）和3）定义新的目标和途径，以调节基于肿瘤细胞的敏感性和基于抗体宿主宿主的敏感性和对抗体的宿主免疫学（AIM 3）。这些结果将引起肿瘤免疫学领域的共鸣。相关性：单克隆抗体（MAB）是许多肿瘤类型的有用治疗方法，但是需要新的方法来改善治疗结果。我们旨在提高mAb直接杀死癌细胞的能力，并刺激人体的免疫学系统，以便可以对癌症进行免疫以防止或延迟继电器或疾病恶化。