Exploring biomarkers of clinical benefit to VEGFR inhibitor combined with PD-L1 inhibitor in recurrent/metastatic Adenoid Cystic Carcinoma

探索 VEGFR 抑制剂联合 PD-L1 抑制剂治疗复发/转移性腺样囊性癌临床获益的生物标志物

• 批准号: 10525029
• 负责人: Renata Ferrarotto
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525029
• 关键词: Address; Adenoid Cystic Carcinoma; Biological; Biological Markers; Blood; Blood specimen; CD8-Positive T-Lymphocytes; Cells; Clinical; Clinical Trials; Clone Cells; Combined Modality Therapy; Computer Analysis; Cytometry; Data; Disease; Endothelial Growth Factors Receptor; Evaluable Disease; Exhibits; FDA approved; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic Determinism; Genetic Transcription; Genomics; Gland; Goals; Head and Neck Cancer; Head and neck structure; Heterogeneity; Image; Immune; Immune checkpoint inhibitor; Immunologic Markers; Immunologics; Knowledge; Lead; Local Therapy; Lymphocyte; Malignant Neoplasms; Mediating; Metastatic/Recurrent; Mutation; NOTCH1 gene; PDL1 inhibitors; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Population; Pre-Clinical Model; Prognosis; Progressive Disease; Protein Tyrosine Kinase; Publishing; Receptor Protein-Tyrosine Kinases; Recurrence; Refractory; Reporting; Research Personnel; Resistance; Role; Salivary Gland Neoplasms; Salivary Glands; Sampling; Stains; Stratification; Systemic Therapy; T cell receptor repertoire sequencing; T-Lymphocyte; TNFSF15 gene; Testing; Tumor Markers; Tumor Tissue; Tyrosine Kinase Inhibitor; Up-Regulation; VEGFA gene; VTCN1 gene; Vascular Endothelial Growth Factors; anti-CTLA4; anti-PD-1; anti-PD-L1 antibodies; biomarker discovery; chemotherapy; cohort; efficacy evaluation; exome sequencing; immunological status; immunoregulation; inhibitor; insight; mRNA sequencing; molecular subtypes; overexpression; personalized care; phase II trial; preservation; protein expression; proteogenomics; response; standard of care; targeted agent; targeted treatment; therapeutically effective; transcriptome sequencing; tumor; tumor-immune system interactions

Adenoid Cystic Carcinoma (ACC), the 2nd most common salivary gland tumor, is chemotherapy-refractory and there is no standard of care treatment for patients with recurrent/metastatic (R/M) disease, highlighting a major clinical unmet need. Vascular endothelial growth factor receptor (VEGFR) inhibitors are frequently used to treat ACC, but render mostly disease stabilization. ACC is also resistant to single agent immune checkpoint inhibitors (ICI), consistent with its low tumor mutational burden (TMB) and overall uninflamed tumor immune microenvironment (TIME). To test if the immunomodulatory role of anti-VEGFR therapy can enhance ICI efficacy and overcome resistance to VEGFR inhibitor monotherapy, we are conducting an investigator-initiated phase II trial, where progressing R/M ACC patients receive axitinib (a VEGFR tyrosine kinase inhibitor) and avelumab (anti-PD-L1 antibody). Study accrual has recently completed with 28 patients evaluable for the efficacy analysis. Interim results revealed an overall response rate of 18% (5/28) per RECIST 1.1, which is superior over VEGFR or ICI monotherapy, and a clinical benefit rate, defined as objective response or disease stability > 6 months, of 50%. Recently, we have conducted a comprehensive proteogenomic analysis of 54 ACC which revealed two distinct subtypes ACC-I and ACC-II. ACC-I is enriched with NOTCH1 activating mutations and MYC overexpression and is associated with poor prognosis while ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases and longer patient survival. Thus far, IHC tumor staining for P63/MYC is available for 22 of 28 trial patients; 12 are ACC-I and 10 are ACC-II demonstrating significant representation of both ACC molecular subtypes. Computational analysis of RNA-seq data of our published cohort with 54 ACC suggested that the ACC-I subtype has a distinct TIME with increased CD8 T cells, along with upregulation of immune suppressive markers. On the basis of our intriguing data, we hypothesize 1) genomic heterogeneity is associated with differential responses to axitinib/avelumab in R/M ACC, and 2) distinct ACC immune landscape and T cell attributes are associated with the clinical outcomes of patients treated with axitinib/avelumab. We will test these hypotheses leveraging the unique tumor tissue and blood from our trial with two aims: 1) Identify genetic determinants of clinical benefit to axitinib and avelumab in ACC. Using the baseline tumors (n=28), we will conduct whole exome sequencing (seq) and RNA-seq and assess if any specific gene alterations, TMB or gene expression profile are associated with benefit. 2) Assess stroma and immunologic determinants of clinical benefit to axitinib and avelumab in ACC. We will examine ACC TIME composition using imaging mass cytometry and determine if the composition of the TIME correlates with clinical benefit. We will also assess tumor-associated T-cell attributes via baseline tumors TCR-seq and circulated T-cell attributes via TCR-seq of paired blood (baseline and on-treatment) and correlate with clinical benefit. Collectively, this project may lead to biomarker discovery and stratification of R/M ACC patients who can benefit from ICI+ anti-angiogenic therapy.

腺样囊性癌（ACC）是第二大最常见的唾液腺肿瘤，是化学疗法 - 饮食性疗法， 对于复发/转移性（R/M）疾病的患者，没有护理水平治疗，强调了一个主要的护理治疗 临床未满足的需求。血管内皮生长因子受体（VEGFR）抑制剂经常用于治疗 ACC，但主要是疾病稳定。 ACC还对单药免疫检查点抑制剂有抵抗力 （ICI），与其低肿瘤突变负担（TMB）和整体无炎性肿瘤免疫一致 微环境（时间）。测试抗VEGFR疗法的免疫调节作用是否可以提高ICI功效 并克服对VEGFR抑制剂单一疗法的耐药性，我们正在进行研究者引起的II期 试验，进展的R/M ACC患者接受Axitinib（VEGFR酪氨酸激酶抑制剂）和AVELUMAB （抗PD-L1抗体）。研究额最近完成了28名可评估疗效分析的患者。 临时结果显示，每个recist 1.1的总反应率为18％（5/28），比VEGFR优于VEGFR 或ICI单一疗法和临床益处，定义为客观反应或疾病稳定性> 6个月的疾病稳定性 50％。最近，我们对54 ACC进行了全面的蛋白质组分析，该分析显示了两个 独特的亚型ACC-I和ACC-II。 ACC-I充满Notch1激活突变和MYC 过表达，与预后不良有关，而ACC-II表现出TP63和受体的上调 酪氨酸激酶和更长的患者存活。到目前为止，P63/MYC的IHC肿瘤染色可用于28中的22个 试验患者； 12个是ACC-I，而ACC-II则表现出两个ACC分子的显着表示 亚型。我们已发表的54 ACC的RNA-seq数据的计算分析表明 ACC-I亚型具有不同的时间，CD8 T细胞增加，以及免疫抑制的上调 标记。根据我们有趣的数据，我们假设1）基因组异质性与 R/M ACC中对Axitinib/avelumab的差异反应，以及2）不同的ACC免疫景观和T细胞 属性与用Axitinib/avelumab治疗的患者的临床结局有关。我们将测试这些 假设利用我们试验的独特肿瘤组织和血液，两个目的：1）确定遗传 ACC中对Axitinib和Avelumab的临床益处的决定因素。使用基线肿瘤（n = 28），我们将 进行整个外显子组测序（SEQ）和RNA-seq，并评估是否有任何特定基因改变，TMB或基因 表达概况与收益相关。 2）评估临床益处的基质和免疫决定因素 在ACC中进行Axitinib和Avelumab。我们将使用成像质量细胞术和 确定时间的组成是否与临床益处相关。我们还将评估与肿瘤相关的 通过基线肿瘤TCR-SEQ和通过配对血的TCR-Seq循环的T-Cell属性TCR-Seq和TCEL的属性 （基线和治疗），并与临床益处相关。总体而言，这个项目可能会导致生物标志物 可以从ICI+抗血管生成疗法中受益的R/M ACC患者的发现和分层。