Project 3: HHLA2 as a THerapeutic Target in RCC

项目 3：HHLA2 作为 RCC 的治疗靶点

基本信息

批准号：
10206027
负责人：
David McDermott
金额：
$ 28.41万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-18 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10206027
关键词：
Antibodies Antitumor Response B-Lymphocytes Binding Biological Markers Blocking Antibodies CD28 gene CTLA4 gene Cell physiology Cells Clear cell renal cell carcinoma Clinical Clinical Research Clinical Trials Dana-Farber Cancer Institute Data Development Endogenous Retroviruses Family member Goals Grant Human Immune Immune checkpoint inhibitor Immune response Immunologist Immunotherapy In Vitro Industry Collaboration Investigation Malignant Neoplasms Modeling Monoclonal Antibodies Natural Killer Cells PD-1 blockade PD-1 inhibitors Pathway interactions Patient Agents Patients Phase 1/1b Clinical Trial Phase I Clinical Trials Population Pre-Clinical Model Primates Proteins Reagent Regulation Regulatory Pathway Renal carcinoma Research Personnel Resistance Resistance development Specimen T-Cell Activation T-Lymphocyte Testing Therapeutic Agents Therapeutic antibodies Toxic effect anti-PD-1/PD-L1 anti-PD1 therapy anti-tumor immune response base cancer therapy clinically significant immune checkpoint in vivo in vivo Model neoplastic cell preservation pressure programmed cell death ligand 1 programmed cell death protein 1 receptor response therapeutic target tumor microenvironment tumor progression

项目摘要

Project 3 Summary While immune checkpoint inhibitors (ICI) have revolutionized the treatment of many cancers, including metastatic clear cell renal cell carcinoma (ccRCC), the development of agents that overcome resistance to anti-PD-1/PD-L1 based therapy represents a critical unmet need for ccRCC patients. We have shown that the B7 family member HERV-H LTR-associating 2 (HHLA2) is expressed in the majority of ccRCC and recently have discovered an inhibitory receptor (KIR3DL3) for HHLA2. Monoclonal antibodies that selectively block the HHLA2/KIRDL3 interaction, which we call the HHLA2 Inhibitory Pathway (HIP), could be an important means to enhance anti-tumor immune responses. In this proposal, we will study the expression of HHLA2 and it receptors in kidney cancer on tumor cells and immune cells and the relationship of HHLA2 and PD-L1 expression on tumors cells. Using clinically annotated specimens from clinical trials of patients with ccRCC on anti-PD-1 therapy, we will determine whether HHLA2 expression is associated with lack of response to PD-1 therapy. We will elucidate the regulatory pathways that are similar and different between HHLA2 and PD-L1 to better understand the expression of these immune checkpoints in kidney cancer and how their expression may change over the course of tumor progression and selection pressures. We will identify the optimal reagents for activating T cells and NK cells through the HHLA2:KIR3DL3 pathway in both in vitro and in vivo models. Our results will direct the selection of humanized blocking antibodies of HHLA2 Inhibitory Pathway that will move into primate toxicity and human Phase I clinical trials during year two of this grant.

项目3摘要尽管免疫检查点抑制剂（ICI）彻底改变了许多癌症的治疗转移性透明细胞肾细胞癌（CCRCC），克服抗性的药物的发展基于抗PD-1/PD-L1的疗法代表了CCRCC患者的至关重要的未满足需求。我们已经证明了 B7家庭成员HERV-H LTR-sassociating 2（HHLA2）在大多数CCRC中表达已经发现了HHLA2的抑制受体（KIR3DL3）。单克隆抗体有选择地阻止我们称为HHLA2抑制途径（HIP）的HHLA2/KIRDL3相互作用可能是重要手段增强抗肿瘤免疫反应。在此提案中，我们将研究HHLA2的表达肿瘤细胞和免疫细胞的肾癌受体以及HHLA2和PD-L1的关系在肿瘤细胞上的表达。使用临床注释的CCRC患者临床试验的标本抗PD-1治疗，我们将确定HHLA2表达是否与对PD-1的反应不足有关治疗。我们将阐明HHLA2和PD-L1之间相似且不同的调节途径更好地了解这些免疫检查点在肾癌中的表达以及它们的表达方式如何在肿瘤进展和选择压力的过程中变化。我们将确定最佳试剂在体外和体内模型中，通过HHLA2：KIR3DL3途径激活T细胞和NK细胞。我们的结果将指导HHLA2抑制途径的人性化阻断抗体的选择，该抗体将移动在这笔赠款的第二年中，进入灵长类动物的毒性和人类I期临床试验。