Project 3: HHLA2 as a THerapeutic Target in RCC

项目3摘要 虽然免疫检查点抑制剂（ICI）已经彻底改变了许多癌症的治疗，包括 转移性透明细胞肾细胞癌（ccRCC），克服对 基于抗PD-1/PD-L1的治疗代表了ccRCC患者的关键未满足需求。我们已经证明， B7家族成员HERV-H LTR相关2（HHLA 2）在大多数ccRCC中表达，最近， 已经发现了HHLA 2的抑制性受体（KIR 3DL 3）。单克隆抗体选择性地阻断 HHLA 2/KIRDL 3相互作用，我们称之为HHLA 2抑制通路（HIP），可能是一种重要的手段， 以增强抗肿瘤免疫反应。在本研究中，我们将研究HHLA 2的表达， 肾癌组织中肿瘤细胞和免疫细胞表面HHLA 2受体的表达及其与PD-L1的关系 在肿瘤细胞上的表达。使用来自ccRCC患者临床试验的临床注释标本， 抗PD-1治疗，我们将确定HHLA 2表达是否与PD-1应答缺乏相关 疗法我们将阐明HHLA 2和PD-L1之间相似和不同的调节途径， 更好地了解这些免疫检查点在肾癌中的表达，以及它们的表达如何 随着肿瘤进展和选择压力的变化。我们将确定最佳试剂， 在体外和体内模型中通过HHLA 2：KIR 3DL 3途径激活T细胞和NK细胞。我们 结果将指导选择HHLA 2抑制途径的人源化阻断抗体， 在该资助的第二年期间进入灵长类动物毒性和人类I期临床试验。

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.