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是全球与癌症相关死亡的第三大最常见原因。治愈后的复发率切除率仍然很高，尤其是在包括大肿瘤（> 5厘米）的高风险HCC中，多灶性疾病和具有血管侵袭的肿瘤。 HCC的临床管理进一步复杂化的事实是，目前尚未提供新辅助或辅助疗法。现在，我们也感谢复发是通过免疫介导的机制。为此，观察到增加肿瘤浸润的CD8+ T细胞与在切除的HCC中，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的成纤维细胞（TAM），髓样衍生的抑制细胞（MDSC），T调节细胞（TREG）有助于抗免疫检查点阻滞和HCC预后不良的抵抗力。其他可溶性诸如血管内皮生长因子（VEGF），菌落刺激因子1（CSF-1）和血小板等介体 - 肿瘤细胞也分泌了衍生的生长因子（PDGF），以促进免疫抑制环境。该提议将决定雷莫拉菲尼的多次激酶活性如何补充抗肿瘤的抗肿瘤活性 PD-L1抗体治疗，通过针对与Treg，MDSC和TAM相关性的关键途径有助于抵抗免疫疗法。因此，通过靶向多种激酶来促进这些维护细胞，我们假设再丙替尼将限制它们在微环境中的持久性，并提高其效力在HCC的新辅助设置中的PD-L1封锁。该提议的中心假设是多激酶用雷莫拉非尼抑制将限制HCC肿瘤微环境中的抑制作用，并允许更多免疫检查点阻滞后，可靠的效应子CD8+ T细胞扩展和浸润。这个假设将会通过两个目标进行测试：1：确定雷莫非尼和杜瓦卢马布对抑制性免疫的影响 HCC中的功能。 2：定义新辅助再丙替尼和杜瓦卢马布对趋化因子的影响和HCC肿瘤中的T细胞表型。在当前的建议中，我们将通过申请来推进该领域在术前环境中，这种新颖的高风险HCC组合。使用创新的翻译方法和患者标本从早期到中级HCC，我们将解决抑制之间的关系免疫细胞和CD8+ T细胞子集。这种方法还提供了一个独特的机会来探索机理通过利用配对的组织样品，雷莫非尼和Durvalumab组合在TME中的影响。它将进一步我们对免疫疗法/靶向治疗组合引起的TME变化的了解，有助于了解电阻的机制，并定义改善当前方案的下一步。开发在疾病进展的关键时刻，新的有效的术前全身疗法可能会提供最佳改善长期生存的机会，因此会对HCC的结果产生重大影响。