Project 1: Targeting the PD-1 pathway in HCC

项目1 -概要/摘要 多激酶抑制剂索拉非尼（一线使用）和瑞格非尼（二线使用）已被批准用于 晚期HCC的治疗;然而，总生存期改善不到3个月， 答复率很低（<10%）。切除术和肝移植是HCC的治愈性治疗;然而， 少于20%的HCC患者适合切除，并且早期复发频繁（2年内50%）。 因为HCC中的主要分子改变是不可药物化的，靶向免疫检查点， 因为程序性细胞死亡1（PD-1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）可能是一种免疫调节剂， 有前途的替代战略。抗PD 1药物nivolumab最近被批准用于HCC治疗。与 20%的缓解率，抗PD 1治疗令人鼓舞，为更有效的治疗提供了机会 接近。在切除的HCC样本中，我们发现肿瘤浸润性T细胞表达PD-1和CTLA-4， 被富含检查点配体PD-L1和PD-L2的致密巨噬细胞浸润物包围。虽然增加了 在不可切除的HCC中已经报道了通过靶向PD-1和CTLA-4途径的免疫应答， 免疫治疗策略尚未在新辅助（术前）和辅助（术后）中进行评估 设置.在纳武单抗±伊匹单抗（抗CTLA-4）治疗可切除HCC的初步随机围手术期试验中， 我们观察到2例完全的病理学反应与CD 8 + T细胞浸润的增加有关 和CD 8/Treg比率。根据迄今为止累积的6例患者，没有发生导致延迟的药物相关事件 或取消手术，我们没有遇到3级或4级不良事件。酪氨酸激酶c-MET是 在HCC中过度表达，并且已经开发了多种c-MET抑制剂，并在临床试验中进行了评估， HCC。然而，报告的结果令人失望。我们发现c-MET抑制剂上调PD-L1 在HCC细胞中的表达，其可以允许HCC细胞逃避T细胞杀伤。我们进一步表明， c-MET抑制剂和抗PD-1的组合协同抑制小鼠中的HCC发展。我们长久以来- 术语翻译目标是调节HCC微环境中的免疫细胞以改善患者的结果 晚期HCC或可切除HCC。我们假设新辅助免疫检查点治疗HCC 可以触发免疫反应，这可能导致延迟复发或增加可切除性， 免疫浸润或纤维化分期可影响治疗反应。我们还假设， HCC免疫治疗可以通过同时靶向免疫检查点信号传导和检查点来改善。 分子表达在目标1中，我们提出了一项靶向PD-1 ± CTLA 4的新辅助/辅助临床试验， 手术肝癌患者延迟复发和局部晚期不可切除的肝癌患者增加 可切除性在目标2中，我们将评估新的联合治疗，包括抗PD-1和药物上调， HCC中的PD-L1表达，如c-MET抑制剂。该项目的影响将是增加获得 更多的HCC患者接受手术治疗，并提高晚期HCC患者的总生存率。

Project 1 – SUMMARY/ABSTRACT The multi-kinase inhibitors, sorafenib (first-line use) and regorafenib (second-line use), have been approved for the treatment of advanced HCC; however, the overall survival improves by less than 3 months and the overall response rates are low (<10%). Resection and liver transplantation are curative treatments for HCC; however, less than 20% of HCC patients are eligible for resection and early recurrence is frequent (50% in 2 years). Because the predominant molecular alterations in HCC are not druggable, targeting immune checkpoints such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) may be a promising alternative strategy. The anti-PD1 drug, nivolumab, was recently approved for HCC therapy. With a 20% response rate, anti-PD1 therapy is encouraging, opening opportunities for more effective therapeutic approaches. In resected HCC samples, we found tumor-infiltrating T cells expressing PD-1 and CTLA-4, surrounded by a dense macrophage infiltrate rich in the checkpoint ligands PD-L1 and PD-L2. While increased immune response by targeting PD-1 and CTLA-4 pathways has been reported in unresectable HCC, immunotherapy strategies have not yet been evaluated in neoadjuvant (pre-surgery) and adjuvant (post-surgery) settings. In a pilot randomized perioperative trial with nivolumab ± ipilimumab (anti-CTLA-4) for resectable HCC, we observed complete pathologic responses in 2 cases that correlated with an increase in CD8+ T cell infiltration and CD8/Treg ratio. Based on the 6 patients accrued to date, none had drug related events that led to delaying or canceling surgery and we didn’t encounter grade 3 or 4 adverse events. The tyrosine kinase c-MET is overexpressed in HCC, and multiple c-MET inhibitors have been developed and evaluated in clinical trials in HCC. However, the reported outcomes were disappointing. We showed that c-MET inhibitors upregulate PD-L1 expression in HCC cells, which may allow HCC cells to escape from T cell killing. We further showed that the combination of c-MET inhibitors and anti-PD-1 synergistically suppresses HCC development in mice. Our long- term translational goal is to modulate immune cells in HCC microenvironment to improve outcome in patients with advanced HCC or resectable HCC. We hypothesize that neoadjuvant immune checkpoint therapy in HCC can trigger an immune response which may lead to delay in recurrence or increased resectability, and that immune infiltration or fibrosis stage can affect treatment response. We also hypothesize that the efficacy of HCC immunotherapy can be improved by simultaneously targeting immune checkpoint signaling and checkpoint molecule expression. In Aim 1, we propose a neoadjuvant/adjuvant clinical trial targeting PD-1 ± CTLA4 in surgical HCC patients to delay recurrence and in locally advanced unresectable HCC patients to increase resectability. In Aim 2, we will evaluate novel combination therapies including anti-PD-1 and agents upregulating PD-L1 expression, such as c-MET inhibitors, in HCC. The impact of this project would be increased access to surgery for a larger number of HCC patients and improve overall survival in patients with advanced HCC.