Determinants of immunotherapy response in NASH-Hepatocellular carcinoma

NASH-肝细胞癌免疫治疗反应的决定因素

• 批准号: 10735947
• 负责人: JOSEP M LLOVET
• 金额: $ 47.39万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735947
• 关键词: Animal Model; Architecture; Atlases; BAY 54-9085; Biopsy; CCL15 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; CTNNB1 gene; Cancer Etiology; Cells; Cellular Structures; Clinic; Clinical; Clinical Trials; Coupled; Cultured Tumor Cells; Data; Diabetes Mellitus; Etiology; Exclusion; Fresh Tissue; Generations; Genes; Genomics; Goals; Hepatocarcinogenesis; Heterogeneity; Histologic; Human; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immunologic Surveillance; Immunology; Immunooncology; Immunotherapeutic agent; Immunotherapy; Impairment; Incidence; Knowledge; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of liver; Maps; Mitogen-Activated Protein Kinase Inhibitor; Molecular; Mus; Mutation; Obesity; Organoids; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Positioning Attribute; Prevalence; Primary carcinoma of the liver cells; Probability; Public Health; Refractory; Regulatory T-Lymphocyte; Reproducibility; Resistance; Resolution; Sampling; Subgroup; Systemic Therapy; T-Cell Activation; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Uses; Tissues; Tumor-Infiltrating Lymphocytes; VEGFA gene; Viral; WNT Signaling Pathway; anti-PD-1; anti-PD-L1; anti-PD1 therapy; antitumor effect; bevacizumab; biomarker driven; biomarker identification; candidate marker; cohort; combinatorial; drug testing; experience; gain of function mutation; genetic signature; immune resistance; individualized medicine; inhibitor; insight; matrigel; molecular marker; mortality; mouse model; neoplastic cell; neutrophil; nonalcoholic steatohepatitis; objective response rate; patient stratification; predicting response; preservation; programmed cell death protein 1; prospective; reconstitution; resistance mechanism; response; response biomarker; single cell technology; single-cell RNA sequencing; standard of care; synergism; three dimensional cell culture; tool; transcriptomics; treatment strategy; tumor; tumor microenvironment

PROJECT SUMMARY / ABSTRACT Hepatocellular carcinoma (HCC) incidence and mortality is increasing in the US and worldwide. Around ~50- 60% of HCC patients will receive systemic therapies. After a decade of primacy of sorafenib, the combination regime of immune checkpoint inhibitor (ICI) atezolizumab (anti-PDL1) with bevacizumab (anti-VEGFA) demonstrated superior clinical benefits (median survival of ~19 months) and has become the standard of care. However, the rate of objective response remains at ~30%. In parallel, our group demonstrated that 1) HCC etiology differentially impacts outcome with patients with HCC deriving from non-alcoholic steatohepatitis (NASH) benefitting significantly less from immunotherapy; 2) Dysfunctional CD8 cells are implicated in the underlying mechanism of resistance in NASH-HCC; 3) Newly generated gene signatures predict response to ICI; and 4) The immune excluded class is driven by Wnt signaling/CTNNB1 mutations in HCC and, thus discovered KIT/MAPK/Wnt inhibitors combined with ICI are adequate strategies to rescue this mechanism of immune- evasion. Our central hypothesis is that such decreased response to ICIs in patients with NASH-HCC can be reverted therapeutically using combinations of ICI and KIT/MAPK/Wnt signaling blockers; and candidate biomarkers of response can be identified and validated. Thus, the overarching goal of this proposal is to gain further insight into mechanisms of both NASH-HCC immune response and resistance via state-of-the-art single cell technologies, so as to identify biomarkers and overcome resistance through the rational testing of combinatorial immunotherapeutic strategies, which could eventually increase the number of HCC patients deriving clinical benefit from immunotherapy. To accomplish this goal, we seek to achieve the following specific aims: 1) To map the immune cell microenvironment in human NASH-HCC by using single cell-based approaches and high-resolution spatial transcriptomics; 2) To identify biomarkers predicting response and resistance to the combination of atezolizumab plus bevacizumab in human NASH-HCC by testing identified gene signatures and molecular markers of response (using transcriptomics and mutational profiling), as well as spatial transcriptomics; 3) To develop therapeutic strategies to overcome ICI resistance in NASH-HCC using specific patient-derived organoids with immune component and mouse models that recapitulate the human NASH-HCC microenvironment. These hypothesis-driven strategies include testing drugs blocking key pathways of immune evasion (Wnt) in combination with ICI. The pursuit of these aims will be coupled with our expertise in NASH- related hepatocarcinogenesis, genomics and transcriptomics, single-cell based technologies, immuno-oncology, generation of organoids reconstituted with TILs and mouse modeling. We expect that our proposal will bring precision immune-oncology closer to the clinics, will promote clinical trials including KIT/MAPK/WNT inhibitors with promise of significant benefit to the outcomes of HCC patients. Overall, our discoveries will create a paradigm shift in the field of NASH-HCC.

项目摘要/摘要 肝细胞癌（HCC）的发病率和死亡率在美国和世界范围内不断增加。约50- 60%的HCC患者将接受全身治疗。在索拉非尼占据主导地位十年后， 免疫检查点抑制剂（ICI）atezolizumab（抗PDL 1）联合贝伐珠单抗（抗VEGFA）方案 证明了上级临床获益（中位生存期约为19个月），并已成为标准治疗。 然而，客观缓解率仍约为30%。与此同时，我们的研究小组证明：1）HCC 病因学对非酒精性脂肪性肝炎（NASH）导致的HCC患者的结局有不同影响 从免疫治疗中获益显著减少; 2）功能障碍的CD 8细胞与潜在的免疫缺陷有关。 NASH-HCC中的抗性机制; 3）新产生的基因特征预测对ICI的应答;和4） 免疫排斥类由HCC中的Wnt信号传导/CTNNB 1突变驱动，因此发现 KIT/MAPK/Wnt抑制剂与ICI组合是拯救这种免疫抑制机制的适当策略。 逃避我们的中心假设是NASH-HCC患者对ICI的反应降低可能是 使用ICI和KIT/MAPK/Wnt信号传导阻断剂的组合在治疗上逆转;和 可以鉴定和验证反应的生物标志物。因此，该提案的总体目标是获得 通过最先进的单克隆抗体进一步深入了解NASH-HCC免疫应答和抗性的机制， 细胞技术，以确定生物标志物，并通过合理的测试克服耐药性， 组合免疫策略，这可能最终增加HCC患者的数量 从免疫疗法中获得临床益处。为了实现这一目标，我们努力实现以下具体目标： 目的：1）利用基于单细胞的方法绘制人NASH-HCC中的免疫细胞微环境 和高分辨率空间转录组学; 2）鉴定预测对药物的反应和抗性的生物标志物， 通过检测鉴定的基因特征，在人NASH-HCC中联合atezolizumab和贝伐珠单抗， 反应的分子标志物（使用转录组学和突变谱），以及空间 3）开发治疗策略以克服NASH-HCC中的ICI抗性，使用特异性转录组学; 具有免疫组分的患者源性类器官和重现人NASH-HCC的小鼠模型 微环境这些假设驱动的策略包括测试阻断免疫调节关键途径的药物。 逃避（Wnt）与ICI的组合。这些目标的追求将与我们在NASH方面的专业知识相结合， 相关的肝癌发生，基因组学和转录组学，单细胞技术，免疫肿瘤学， 用TIL重建的类器官的产生和小鼠建模。我们希望我们的提议能带来 更接近临床的精确免疫肿瘤学，将促进包括KIT/MAPK/WNT抑制剂在内的临床试验 并有望对HCC患者的结局产生显著益处。总的来说，我们的发现将创造一个 NASH-HCC领域的范式转变。