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: 10676870
• 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/10676870
• 关键词: Address; Adenoid Cystic Carcinoma; Angiogenesis Inhibitors; 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; Local Therapy; Lymphocyte; Malignant Neoplasms; Mediating; Metastatic/Recurrent; Mutation; NOTCH1 gene; PDL1 inhibitors; Patient-Focused Outcomes; Patients; Phenotype; Population; Pre-Clinical Model; Prognosis; Progressive Disease; Publishing; Receptor Protein-Tyrosine Kinases; Recurrence; Refractory; Reporting; Research Personnel; Resistance; Role; Salivary Gland Neoplasms; Salivary Glands; Sampling; Stable Disease; 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; immune modulating agents; 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) 是第二常见的唾液腺肿瘤，化疗难治性且 对于复发/转移 (R/M) 疾病患者，没有标准的护理治疗，这凸显了一个主要问题 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，但主要使疾病稳定。 ACC 还对单药免疫检查点抑制剂具有耐药性 （ICI），与其低肿瘤突变负荷（TMB）和整体未发炎的肿瘤免疫一致 微环境（时间）。测试抗 VEGFR 治疗的免疫调节作用是否可以增强 ICI 疗效 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发起的 II 期试验 试验中，进展的 R/M ACC 患者接受阿西替尼（一种 VEGFR 酪氨酸激酶抑制剂）和 avelumab （抗 PD-L1 抗体）。研究应计最近已完成，有 28 名患者可进行疗效分析评估。 中期结果显示，根据 RECIST 1.1，总体缓解率为 18% (5/28)，优于 VEGFR 或 ICI 单药治疗，以及临床获益率（定义为客观缓解或疾病稳定性 > 6 个月） 50%。最近，我们对 54 ACC 进行了全面的蛋白质组学分析，揭示了两个 不同的亚型 ACC-I 和 ACC-II。 ACC-I 富含 NOTCH1 激活突变和 MYC 过度表达并与不良预后相关，而 ACC-II 表现出 TP63 和受体的上调 酪氨酸激酶和更长的患者生存期。到目前为止，28 例中的 22 例可进行 P63/MYC 的 IHC 肿瘤染色 试验患者； 12 个是 ACC-I，10 个是 ACC-II，展示了两种 ACC 分子的显着代表性 亚型。对我们发表的 54 ACC 队列的 RNA-seq 数据进行计算分析表明 ACC-I 亚型具有独特的 TIME，CD8 T 细胞增加，同时免疫抑制上调 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 属性与接受阿西替尼/阿维鲁单抗治疗的患者的临床结果相关。我们将测试这些 利用我们试验中独特的肿瘤组织和血液的假设有两个目的：1）识别遗传 ACC 中阿西替尼和 avelumab 临床获益的决定因素。使用基线肿瘤 (n=28)，我们将 进行全外显子组测序 (seq) 和 RNA-seq，并评估是否有任何特定基因改变、TMB 或基因 表达谱与益处相关。 2) 评估临床获益的基质和免疫决定因素 ACC 中的阿西替尼和 avelumab。我们将使用成像质谱流式细胞术检查 ACC TIME 组成，并 确定 TIME 的组成是否与临床获益相关。我们还将评估肿瘤相关 通过基线肿瘤 TCR-seq 获得的 T 细胞属性和通过配对血液的 TCR-seq 获得的循环 T 细胞属性 （基线和治疗中）并与临床获益相关。总的来说，该项目可能会产生生物标志物 发现并分层可从 ICI+ 抗血管生成治疗中获益的 R/M ACC 患者。