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)是第二大常见的唾液腺肿瘤，对化疗不敏感。 对于复发/转移(R/M)疾病的患者，没有标准的护理治疗，这突出了一个主要的 临床上未得到满足的需求。血管内皮生长因子受体(VEGFR)抑制剂经常用于治疗 ACC，但大部分情况下病情稳定。ACC对单剂免疫检查点抑制剂也具有抗药性 (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)。检测抗VEGFR治疗的免疫调节作用是否能提高ICI的疗效 并克服对VEGFR抑制剂单一疗法的耐药性，我们正在进行一项由研究人员启动的II阶段 进展期R/M ACC患者接受Axitinib(一种VEGFR酪氨酸激酶抑制剂)和Avelumab的试验 (抗PD-L1抗体)。最近完成了28名患者的研究，可用于疗效分析。 中期结果显示，每个RECIST 1.1的总体应答率为18%(5/28)，优于VEGFR 或ICI单一疗法，以及临床受益率，定义为客观反应或疾病稳定性&6个月， 50%。最近，我们对54例ACC进行了全面的蛋白质组学分析，发现了两个 不同的亚型ACC-I和ACC-II。ACC-I富含NOTCH1激活突变和MYC 过度表达与预后不良有关，而ACC-II显示TP63和受体上调 酪氨酸激酶和更长的患者生存期。到目前为止，28例中有22例进行了p63/myc的IHC肿瘤染色。 试验患者：12例为ACC-I，10例为ACC-II，显示出这两种ACC分子的显著代表性 子类型。对我们发表的54个ACC队列的RNA-SEQ数据的计算分析表明， ACC-I亚型与CD8 T细胞的增加以及免疫抑制的上调有明显的时间差异 记号笔。根据我们耐人寻味的数据，我们假设1)基因组异质性与 在R/M ACC中对Axitinib/Avelumab的不同反应，以及2)不同的ACC免疫格局和T细胞 属性与使用Axitinib/Avelumab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)识别基因 Axitinib和Avelumab在ACC中临床受益的决定因素。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的基因改变，TMB或基因 表达简档与福利相关联。2)评估临床受益的间质和免疫学决定因素 AXITINB和Avelumab在ACC中。我们将使用成像质量细胞仪和 确定时间的构成是否与临床益处相关。我们还将评估与肿瘤相关的 通过配对血液的基线肿瘤TCR-SEQ和循环T细胞属性TCR-SEQ获得的T细胞属性 (基线和正在治疗)，并与临床效益相关。总的来说，这个项目可能会导致生物标记物 ICI+抗血管生成治疗可受益的R/M ACC患者的发现和分层