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: 10467512
• 负责人: Paul G. Thomas
• 金额: $ 73.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467512
• 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; 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; Immunomodulators; Immunotherapy; Laboratory Study; Lead; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Maps; Modeling; Nivolumab; PRKACA gene; Pathway interactions; Patients; Pediatric Oncology; Peptide Vaccines; Peptide/MHC Complex; Peptides; Pharmaceutical Preparations; Pharmacology; 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; arm; base; biobank; cancer therapy; cellular transduction; cytokine; effective therapy; enzyme linked immunospot assay; exhaustion; fusion gene; genomic signature; humanized mouse; immune resistance; immunogenicity; in vivo; inhibitor; innovation; ipilimumab; mouse model; multiplexed imaging; neoantigens; next generation; novel; novel therapeutic intervention; peripheral blood; preservation; prevent; rare cancer; response; safety testing; single-cell RNA sequencing; small molecule inhibitor; standard care; 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 纤维板层肝细胞癌 (FLC) 是一种罕见且通常致命的肝癌，主要影响 没有肝硬化的儿童和年轻人 对于 FLC 尚无批准的全身疗法，通常采用全身疗法。 对其他形式的肝癌开发的治疗方法无效。 DNAJB1 和 PRKACA 被确定为 FLC 中的标志性基因组事件并导致组成型激活 PKAc，但传统小分子抑制剂对 PKAc 对 FLC 的药理抑制作用已被证实 我们小组和其他人之前的工作已经证明新抗原是不可行的。 源自基因融合，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 FLC 患者在融合连接处共享相同的氨基酸序列，从而允许 单一“现成的”新抗原特异性疫苗几乎普遍用于这种癌症。 特定疫苗与其他免疫调节剂（包括 ICI）联合使用最有效 我们的总体假设是针对 DNAJB1- 的新抗原特异性疫苗。 PRKACA 嵌合体将与 ICI 协同作用，在 FLC 中引发特异性抗肿瘤免疫反应。 针对 DNAJB1-PRKACA 嵌合体 (FLC-Vac) 的疫苗与纳武单抗联合的临床试验 和 ipilimumab，用于不可切除的 FLC 患者，我们将进一步确定 FLC-Vac 是否与 ICI 联合治疗。 增加对 DNAJB1-PRKACA 嵌合体具有特异性的新表位特异性 T 细胞的数量 配对预处理和后续处理中输送至肿瘤的外周血。 治疗活检将进一步明确免疫反应和免疫治疗耐药的机制 FLC。我们将使用这些样本来识别 T 细胞受体 (TCR)，该受体对 FLC 融合蛋白具有特异性。 使用我们试验中的 TCR 和未经治疗的内源性反应来确定患者的 HLA 背景。 标本，我们将使用人源化小鼠原位模型来确定处理的相对效率 这些模型将在不同的 MHC 环境中呈现 DNAJB1-PRKACA 融合的特定表位。 涉及 FLC 融合在我们将用原代细胞治疗的肿瘤系内的内源性呈现 用我们确定的 TCR 进行转导，使我们能够比较特定于 TCR 的靶向效率 这项工作可能会为FLC这种肿瘤提供一种新的治疗范例。 目前尚无标准或有效的全身治疗方法，并且对于针对复发性疾病具有重要意义 识别其他免疫抗性肿瘤类型中的“不可成药”驱动基因。 针对 DNAJB1-PRKACA 融合的组合也将为下一代奠定基础 FLC 的临床试验，包括对 DNAJB1-PRKACA 融合具有特异性的过继细胞疗法。