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 纤维板层型肝细胞癌（FLC）是一种罕见且通常致命的肝癌形式，主要影响 没有肝硬化的儿童和年轻人。目前还没有批准的FLC全身治疗方法， 对于其他形式的肝癌开发的治疗方法是难治的。一种嵌合转录本， DNAJB 1和PRKACA被鉴定为FLC中的标志性基因组事件，并导致组成性激活 的PKAc，但药理学抑制PKAc的FLC与传统的小分子抑制剂已被 由于靶向毒性而不可行。我们小组和其他人先前的工作已经证明， 来源于基因融合，包括FLC中的DNAJB 1-PRKACA融合，可以刺激强烈的T细胞应答。 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，这使得FLC的基因突变可能与FLC的基因突变有关。 单一的“现成的”新抗原特异性疫苗几乎普遍用于这种癌症。新抗原- 特异性疫苗与其它免疫调节剂（包括ICI）组合最有效， 防止T细胞耗竭。我们的总体假设是，靶向DNAJB 1的新抗原特异性疫苗- PRKACA嵌合体将与ICI协同在FLC中引发特异性抗肿瘤免疫应答。我们会进行 靶向DNAJB 1-PRKACA嵌合体（FLC-Vac）的疫苗与纳武单抗联合的临床试验 和易普利姆玛，在不可切除的FLC患者中。我们将进一步确定FLC-Vac联合ICI是否 增加了对DNAJB 1-PRKACA嵌合体具有特异性的新表位特异性T细胞的数量。 外周血流向肿瘤。配对预处理和未处理的多重免疫组织化学（IHC） 治疗活检将进一步确定免疫应答和免疫治疗抵抗的机制， FLC。我们将使用这些样品来鉴定FLC融合蛋白特异性的T细胞受体（TCR）。 患者的HLA。使用我们试验中的TCR和未经治疗的患者中发现的内源性反应 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 并在不同的MHC环境中呈递来自DNAJB 1-PRKACA融合体的特异性表位。这些模型将 涉及我们将用原代细胞治疗的肿瘤系内FLC融合的内源性呈递 用我们鉴定的TCR转导，使我们能够比较特异于 对应的融合表位。这项工作可能会为FLC提出一种新的治疗模式，这种肿瘤 没有标准或有效的全身治疗，这将对靶向复发性疾病具有重要意义。 在其他免疫耐药肿瘤类型中的“不可用药”驱动基因。鉴定最佳肽-HLA-TCR 靶向DNAJB 1-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DNAJB 1-PRKACA融合具有特异性的过继细胞疗法。