Preoperative immunotherapy in Hepatocellular Carcinoma

项目概要/摘要： HCC是全球癌症相关死亡的第三大常见原因。治愈后复发率 切除率仍然很高，特别是在高危HCC中，包括大肿瘤（>5 cm）、多灶性疾病和 肿瘤有血管浸润。HCC临床管理的进一步复杂化是目前没有 新辅助疗法或辅助疗法是可用的。我们现在也认识到复发是通过免疫介导的， 机制等支持这一点的是观察到增加的肿瘤浸润性CD 8 + T细胞与肿瘤浸润性T细胞相关。 切除的HCC预后更好，复发率更低。相反，高比例的免疫抑制细胞 包括肿瘤相关的成纤维细胞（TAM）、髓源性抑制细胞（MDSC）、T调节细胞（T细胞 （THBE）导致对免疫检查点阻断的抗性和HCC中的不良预后。其他可溶性 介质如血管内皮生长因子（VEGF）、集落刺激因子1（CSF-1）和血小板- 衍生生长因子（PDGF）也由肿瘤细胞分泌以促进免疫抑制环境。 该提案将确定瑞戈非尼的多激酶活性如何补充抗肿瘤药物的抗肿瘤活性。 PD-L1抗体治疗，通过靶向与TGFAP、MDSC和TAM相关的关键途径，所有这些途径 有助于抵抗免疫疗法。因此，通过靶向促进这些维持的多种激酶， 细胞，我们假设瑞戈非尼将限制其在微环境中的持久性，并提高其疗效。 PD-L1阻断在HCC新辅助治疗中的应用这个提议的中心假设是多激酶 瑞戈非尼的抑制作用将限制HCC肿瘤微环境中的抑制特征， 在免疫检查点阻断后，稳健的效应CD 8 + T细胞扩增和浸润。这一假设将 通过两个目的进行测试：1：确定瑞戈非尼和度伐鲁单抗对抑制性免疫应答的影响。 HCC的特征。2：确定新辅助瑞戈非尼和durvalumab对趋化因子特征的影响 和浸润性T细胞表型。在目前的提案中，我们将通过应用 这种新的组合在高危HCC的术前设置。使用创新的翻译方法 和患者标本从早期到中期阶段肝癌，我们将解决之间的关系抑制 免疫细胞和CD 8 + T细胞亚群。这种方法也提供了一个独特的机会，探索机械 通过使用配对组织样品，研究瑞戈非尼和德瓦鲁单抗组合在TME中的作用。将进一步 我们对免疫疗法/靶向疗法组合诱导的TME变化的了解， 了解耐药机制，并确定改进当前方案的下一步措施。开发一 在疾病进展的这个关键点，新的有效的术前系统治疗可能提供最好的 提高长期生存率的机会，因此对HCC的结局有显著影响。

Project Summary/Abstract: HCC is the third most common cause of cancer-related death worldwide. Recurrence rates after curative resection remain high, especially in high-risk HCC which includes large tumors (>5 cm), multifocal disease and tumors with vascular invasion. Further complicating clinical management of HCC is the fact that currently no neoadjuvant or adjuvant therapies are available. We now also appreciate that recurrence is mediated via immune mechanisms. In support of this are observations that increased tumor infiltrating CD8+ T cells are associated with better outcomes and less recurrence in resected HCC. Conversely, high proportions of immune inhibitory cells including tumor associated fibroblast (TAMs), myeloid derived suppressor cells (MDSCs), T regulatory cells (Tregs) contribute to resistance to immune checkpoint blockade and poor prognosis in HCC. Other soluble mediators such as vascular endothelial growth factor (VEGF), colony stimulating factor 1 (CSF-1), and platelet- derived growth factor (PDGF), are also secreted by tumor cells to promote an immunosuppressive environment. This proposal will determine how the multikinase activity of regorafenib complements antitumor activity of anti- PD-L1 antibody therapy, by targeting key pathways of relevance to Tregs, MDSCs, and TAMs, all of which contribute to resistance to immunotherapy. Thus, by targeting multiple kinases that foster maintenance of these cells, we postulate regorafenib will limit their persistence in the microenvironment and improve the efficacy of PD-L1 blockade in the neoadjuvant setting of HCC. The central hypothesis of this proposal is that multikinase inhibition with regorafenib will limit suppressive features in the HCC tumor microenvironment and permit more robust effector CD8+ T cell expansion and infiltration upon immune checkpoint blockade. This hypothesis will be tested via two aims: 1: To determine the effects of regorafenib and durvalumab on suppressive immune features in HCC. 2: To define the impact of neoadjuvant regorafenib and durvalumab on chemokine signatures and infiltrating T cell phenotypes in HCC tumors. In the current proposal, we will advance the field by applying this novel combination in high-risk HCC in the preoperative setting. Using innovative translational approaches and patient specimens from early to intermediate stage HCC, we will address relationships between inhibitory immune cells and CD8+ T cell subsets. This approach also provides a unique opportunity to explore mechanistic effects of the regorafenib and durvalumab combination in the TME by utilizing paired tissue samples. It will further our knowledge of changes in the TME induced by the immunotherapy/targeted therapy combination, help understand mechanisms of resistance and define the next steps in improving the current regimen. Developing a new and effective preoperative systemic therapy at this critical point in disease progression may provide the best chance for improved long-term survival and therefore have a significant impact on the outcome of HCC.