Preoperative immunotherapy in Hepatocellular Carcinoma

肝细胞癌的术前免疫治疗

基本信息

批准号：
10578074
负责人：
Mehmet Akce
金额：
$ 21.95万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578074
关键词：
Adjuvant Adjuvant Therapy Antibody Therapy Attention BRAF gene Biological Assay Biopsy Biopsy Specimen Blood Blood Vessels Blood specimen CD8-Positive T-Lymphocytes CD8B1 gene CSF1R gene CXCL10 gene CXCR3 gene Cancer Etiology Cancer Patient Cell Maintenance Cells Cessation of life Clinical Clinical Data Clinical Management Clinical Trials Combined Modality Therapy Communities Complement Curative Surgery Cytometry Data Disease Disease Progression Environment Enzyme-Linked Immunosorbent Assay Excision Fibroblast Growth Factor Receptor 1 Fibroblasts Fostering Funding Future Human Immune Immune Targeting Immune system Immunofluorescence Immunologic Immunotherapy Infiltration Infrastructure Institution Invaded KDR gene Keratin-19 Knowledge Leukocytes Lymphocyte Macrophage Colony-Stimulating Factor Malignant Epithelial Cell Mediating Mediator Memory Myeloid Cells Myeloid-derived suppressor cells Neoadjuvant Therapy Oncogenic Oncology Operative Surgical Procedures Oral Outcome PD-1/PD-L1 PD-L1 blockade PDGFRB gene Pathway interactions Patients Perioperative Pharmaceutical Preparations Phenotype Phosphotransferases Physicians Platelet-Derived Growth Factor Prevention Primary carcinoma of the liver cells Production Prognosis Proteins Proto-Oncogene Protein c-kit Recurrence Regimen Regulatory T-Lymphocyte Reporting Research Resected Resistance Risk STAT protein Signal Pathway Specimen Systemic Therapy T cell infiltration T cell receptor repertoire sequencing T-Lymphocyte T-Lymphocyte Subsets TEK gene TIE-2 Receptor Testing Therapeutic Studies Tissue Sample Tissues Transcript Translating Transplantation Surgery Tumor Antigens Tumor-associated macrophages Vascular Endothelial Growth Factors anti-PD-L1 anti-PD-L1 antibodies anti-PD1 antibodies anticancer research chemokine chemotherapy combinatorial cost cytokine design digital disorder control exhaust high risk immune checkpoint blockade improved inhibitor innovation interdisciplinary approach interest liver cancer model malignant stomach neoplasm mouse model multidisciplinary neoplastic cell next generation novel patient subsets pembrolizumab phase II trial pre-clinical preclinical study programs receptor resistance mechanism response sample collection stem synergism synthetic polymer Bioplex targeted treatment translational approach tumor tumor microenvironment

项目摘要

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.

项目摘要/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，特别是在高风险 HCC 中，其中包括大肿瘤（> 5 cm）、多灶性病变和具有血管侵犯的肿瘤。使 HCC 临床管理进一步复杂化的事实是，目前尚无可采用新辅助或辅助治疗。我们现在也认识到复发是通过免疫介导的机制。支持这一观点的观察结果是，肿瘤浸润性 CD8+ T 细胞的增加与切除的 HCC 具有更好的结果和更少的复发。相反，高比例的免疫抑制细胞包括肿瘤相关成纤维细胞 (TAM)、骨髓源性抑制细胞 (MDSC)、T 调节细胞 (Treg) 有助于抵抗免疫检查点阻断并导致 HCC 预后不良。其他可溶性血管内皮生长因子 (VEGF)、集落刺激因子 1 (CSF-1) 和血小板等介质衍生生长因子（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 抗体疗法，通过靶向与 Tregs、MDSC 和 TAM 相关的关键通路，所有这些有助于免疫治疗的抵抗。因此，通过靶向多种激酶，促进这些激酶的维持细胞，我们假设瑞戈非尼将限制它们在微环境中的持久性并提高其功效 HCC 新辅助治疗中的 PD-L1 阻断。该提案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，并允许更多免疫检查点阻断后，效应 CD8+ T 细胞强劲扩张和浸润。这个假设将通过两个目的进行测试： 1：确定瑞戈非尼和杜瓦鲁单抗对抑制性免疫的影响 HCC 的特征。 2：定义新辅助瑞戈非尼和度瓦鲁单抗对趋化因子特征的影响以及 HCC 肿瘤中的浸润性 T 细胞表型。在当前的提案中，我们将通过应用来推进该领域这种新颖的组合在术前治疗高风险 HCC 中。使用创新的转化方法以及从早期到中期 HCC 的患者标本，我们将解决抑制性之间的关系免疫细胞和 CD8+ T 细胞亚群。这种方法还提供了探索机制的独特机会利用配对组织样本研究瑞戈非尼和杜瓦鲁单抗组合在 TME 中的效果。它将进一步我们对免疫疗法/靶向疗法组合引起的 TME 变化的了解，有助于了解耐药机制并确定改进当前治疗方案的后续步骤。开发一个在疾病进展的这个关键时刻，新的、有效的术前全身治疗可能提供最好的治疗改善长期生存的机会，因此对 HCC 的结果有重大影响。