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方法，包括 转移性肾透明细胞癌(CcRCC)是指克服抗药性药物的发展 以抗PD-1/PD-L1为基础的治疗代表着ccRCC患者尚未得到满足的关键需求。我们已经证明了 B7家族成员HERV-H LTR-Associating 2(HHLA2)在大多数肾细胞癌和新近发现的肾细胞癌中表达 发现了HHLA2的抑制性受体(KIR3DL3)。选择性地阻断血管内皮细胞 HHLA2/KIRDL3相互作用，我们称之为HHLA2抑制通路(HIP)，可能是一种重要的手段 增强抗肿瘤免疫反应。在这个方案中，我们将研究HHLA2和它的表达 肾癌肿瘤细胞和免疫细胞上的受体及HHLA2和PD-L1的关系 在肿瘤细胞上表达。使用来自慢性肾细胞癌患者临床试验的带临床注释的标本 抗PD-1治疗，我们将确定HHLA2的表达是否与PD-1的反应不足有关 心理治疗。我们将阐明HHLA2和PD-L1之间相似和不同的调控途径 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 在肿瘤进展和选择压力的过程中发生变化。我们将确定用于治疗的最佳试剂 在体内外模型中通过HHLA2：KIR3DL3途径激活T细胞和NK细胞。我们的 研究结果将指导HHLA2抑制通路人源化封闭抗体的选择 在这笔赠款的第二年进行灵长类毒性和人类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.