Neoantigen-specific T cell responses for Fibrolamellar Hepatocellular Carcinoma

纤维板层肝细胞癌的新抗原特异性 T 细胞反应

• 批准号: 10609918
• 负责人: Paul G. Thomas
• 金额: $ 70.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609918
• 关键词: Active Sites; Adolescent and Young Adult; Adoptive Cell Transfers; Adult; Affect; Amino Acid Sequence; Area; Biochemical; Biopsy; Biopsy Specimen; Blood; Cancer Center; Catalytic Domain; Cell Therapy; Cells; Child; Chimera organism; Chimeric Proteins; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Code; Collection; Combined Modality Therapy; Cyclic AMP-Dependent Protein Kinases; Cytometry; Cytotoxic T-Lymphocytes; Data; Effectiveness; Environment; Epitopes; Event; Exons; Fibrolamellar Hepatocellular Carcinoma; Foundations; Frequencies; Gene Fusion; Genes; Goals; Human; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immune system; Immunohistochemistry; Immunotherapy; Institution; Laboratory Study; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Maps; Modeling; Nivolumab; PRKACA gene; Pathway interactions; Patients; Pediatric Oncology; Peptide Vaccines; Peptide/MHC Complex; Peptides; Pharmaceutical Preparations; Phosphotransferases; Pilot Projects; Population; Pre-Clinical Model; Primary Malignant Neoplasm of Liver; Recurrence; Refractory; Resistance; Resolution; Safety; Saint Jude Children' s Research Hospital; Sampling; Specificity; Specimen; Stains; Systemic Therapy; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; T-cell receptor repertoire; Tissues; Toxic effect; Transcript; Universities; Unresectable; Vaccines; Work; anti-tumor immune response; antigen-specific T cells; arm; biobank; cancer therapy; cellular transduction; cytokine; effective therapy; enzyme linked immunospot assay; exhaustion; fusion gene; genomic signature; humanized mouse; immune modulating agents; immune resistance; immunogenicity; in vivo; inhibitor; innovation; ipilimumab; mouse model; multiplexed imaging; neoantigens; next generation; novel; novel therapeutic intervention; peripheral blood; pharmacologic; preservation; prevent; rare cancer; response; safety testing; single-cell RNA sequencing; small molecule inhibitor; standard care; synergism; transcriptome; tumor; tumor microenvironment; vaccine development; young adult

Project Abstract Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal form of liver cancer that primarily affects children and young adults without cirrhosis. There are no approved systemic therapies for FLC, and it is usually refractory to treatment approaches developed for other forms of liver cancer. A chimeric transcript between DNAJB1 and PRKACA was identified as a signature genomic event in FLC and leads to constitutive activation of PKAc, but pharmacological inhibition of PKAc for FLC with traditional small molecule inhibitors has been infeasible due to on-target toxicity. Prior work from our group and others has demonstrated that neoantigens derived from gene fusions, including the DNAJB1-PRKACA fusion in FLC, can stimulate strong T cell responses. Furthermore, all patients with FLC share an identical amino acid sequence at the fusion junction, allowing a single “off the shelf” neoantigen-specific vaccine to be utilized nearly universally for this cancer. Neoantigen- specific vaccines are most effective in combination with other immunomodulatory agents including ICIs to prevent T cell exhaustion. Our overall hypothesis is that a neoantigen-specific vaccine targeting the DNAJB1- PRKACA chimera will synergize with ICIs to elicit a specific antitumor immune response in FLC. We will conduct a clinical trial of a vaccine targeting the DNAJB1-PRKACA chimera (FLC-Vac), in combination with nivolumab and ipilimumab, in patients with unresectable FLC. We will further determine if FLC-Vac combined with ICIs increases the number of neoepitope-specific T cells with specificity for the DNAJB1-PRKACA chimera in the peripheral blood that traffic to the tumor. Multiplex immunohistochemistry (IHC) on paired pretreatment and on- treatment biopsies will further define the mechanisms of immune response and resistance to immunotherapy in FLC. We will use these samples to identify T cell receptors (TCRs) specific for the FLC fusion protein in the context of the patient's HLA. Using TCRs from our trial and from endogenous responses identified in untreated specimens, we will use humanized mouse orthotopic models to determine the relative efficiency of processing and presenting specific epitopes from the DNAJB1-PRKACA fusion in diverse MHC contexts. These models will involve the endogenous presentation of the FLC fusion within tumor lines that we will treat with primary cells transduced with our identified TCRs, allowing us to compare the targeting efficiency of TCRs specific for the corresponding fusion epitopes. This work may advance a novel treatment paradigm for FLC, a tumor for which there is no standard or effective systemic therapy, and will have important implications for targeting recurrent ”undruggable” driver genes in other immune-resistant tumor types. Identifying optimal peptide-HLA-TCR combinations for targeting the DNAJB1-PRKACA fusion will also lay the groundwork for the next generation clinical trials for FLC, including adoptive cell therapies with specificity for the DNAJB1-PRKACA fusion.

项目摘要 纤维状肝细胞癌（FLC）是一种罕见且经常致命的肝癌形式，主要影响 没有肝硬化的儿童和年轻人。 FLC没有批准的全身疗法，通常是 针对其他形式的肝癌的治疗方法的难治性。嵌合笔录 DNAJB1和PRKACA被确定为FLC中的签名基因组事件，并导致本构激活 PKAC，但使用传统小分子抑制剂对PKAC对PKAC的药理抑制作用已是 由于靶向毒性而不可行。我们小组和其他人的先前工作证明了新抗原 源自基因融合物，包括FLC中的DNAJB1-PRKACA融合，可以刺激强烈的T细胞反应。 此外，所有患有FLC的患者在融合连接处共享相同的氨基酸序列，从而允许 单一的“ Off the Besl架”新抗原特异性疫苗几乎被普遍用于该癌症。 特定的疫苗最有效地与其他免疫调节剂结合使用，包括ICIS 防止T细胞耗尽。我们的总体假设是针对DNAJB1-的新抗原特异性疫苗 Prkaca Chimera将与ICIS协同作用，以引起FLC中特定的抗肿瘤免疫增强响应。我们将进行 针对DNAJB1-PRKACA嵌合体（FLC-VAC）的疫苗的临床试验，结合Nivolumab 和ipilimumab，不可切除的FLC患者。我们将进一步确定FLC-VAC是否与ICIS合并 增加了具有特异性的neoeppitope特异性T细胞的数量 向肿瘤流动的外围血。多重免疫组织化学（IHC）在配对预处理和on- 治疗活检将进一步定义免疫响应的机制和对免疫疗法的抵抗 flc。我们将使用这些样品来识别针对FLC融合蛋白特异的T细胞受体（TCR） 患者HLA的背景。使用我们试验的TCR和未经处理的内源反应中的内源反应 标本，我们将使用人源化的鼠标原位模型来确定处理的相对效率 并在潜水员MHC环境中呈现DNAJB1-PRKACA融合的特定表位。这些模型将 涉及在肿瘤线中使用FLC融合的内源性表现，我们将用原代细胞治疗 与我们确定的TCR一起传递，使我们能够比较特有的TCR的靶向效率 相应的融合表位。这项工作可能会推动针对FLC的新型治疗范式，肿瘤为此 没有标准或有效的全身疗法，将对靶向重复具有重要意义 其他免疫肿瘤类型中的“不良”驱动基因。识别最佳肽-HLA-TCR 靶向DNAJB1-PRKACA融合的组合也将为下一代奠定基础 FLC的临床试验，包括具有特异性DNAJB1-PRKACA融合的适应性细胞疗法。