HLA B44 motif neoepitopes in NSCLC: Evaluating their effects on the TME and adding them to established markers in a model to predict durable benefit from PD- 1 inhibition with and without chemotherapy

NSCLC 中的 HLA B44 基序新表位：评估它们对 TME 的影响，并将它们添加到模型中已建立的标记中，以预测有或没有化疗的 PD-1 抑制的持久益处

• 批准号: 10681851
• 负责人: EDWARD B GARON
• 金额: $ 62.08万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681851
• 关键词: Adjuvant Chemotherapy; Agreement; Algorithms; Alleles; Amino Acid Substitution; Amino Acids; Antigen Presentation; Antigens; Binding; Biological Markers; Biopsy; Cancer Etiology; Cancer Patient; Cessation of life; Charge; Clinical; Clinical Data; Combination Drug Therapy; Data; Development; Disease; Disease Progression; Disease-Free Survival; Dissociation; Early identification; Electrostatics; Epidermal Growth Factor Receptor; Ethnic Population; Evaluation; Event; Gene Expression; HLA Antigens; Immune; Immune response; Immunofluorescence Immunologic; Immunologic Markers; Immunologics; In complete remission; Inflammatory; Lead; Ligands; Malignant neoplasm of lung; Methods; Minority; Mismatch Repair Deficiency; Modeling; Mutation; Neoadjuvant Therapy; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Outcome; Pathologic; Patient Selection; Patients; Peptides; Peripheral Blood Mononuclear Cell; Population; Positioning Attribute; Predictive Value; Prevalence; Role; Sampling; Slide; Specimen; Testing; The Cancer Genome Atlas; Therapeutic; Tumor-Infiltrating Lymphocytes; United States; Up-Regulation; anti-tumor immune response; antigen binding; bak protein; biomarker evaluation; biomarker identification; chemotherapy; clinical care; clinically relevant; combinatorial; exome sequencing; genetic signature; immune checkpoint; improved; inhibitor; neoantigens; outcome prediction; patient population; predict clinical outcome; predictive marker; programmed cell death ligand 1; programmed cell death protein 1; racial population; response; single-cell RNA sequencing; spatial relationship; standard of care; transcriptomics; treatment strategy; tumor; tumor microenvironment

PROJECT SUMMARY Lung cancer is the leading cause of cancer related deaths in the United States and the World. We recently demonstrated that programmed cell death 1 (PD-1) inhibitors, which lead to durable responses in a minority of non-small cell lung cancer (NSCLC) patients, have greater efficacy in patients with charged HLA-B binding pockets whose tumors harbor mutation(s) leading to what we have designated as motif neoepitopes. Motif neoepitopes have an amino acid substitution in the second position of a nonamer generating a change in charge from the wild type peptide with the resultant amino acid having a charge opposite from the HLA-B binding pocket. To date, the immunological changes induced by motif neoepitopes have not been explored. We propose a comprehensive evaluation of the underlying mechanism, focusing on patients with HLA-B44 supertype alleles because of the prevalence (approximately 40% of the population) and distribution of HLA-B44 across racial and ethnic groups. We will evaluate HLA-B44 samples in the cancer genome atlas (TCGA) to explore differences in the tumor microenvironment (TME) among patients with or without motif neoepitopes by examining gene expression and cellular composition by slide review and algorithms based on gene expression profiles. We will evaluate surgical specimens from treatment naïve patients with or without HLA-B44 motif neoepitopes and evaluate spatial signatures of the TME by multiplex immunofluorescence (MIF). We will assess multiple sections from each specimen to identify biomarkers most significantly associated with motif neoepitopes. We will further examine immune contextures of the TME associated with motif neoepitopes by single cell RNA-seq analysis. To elucidate the predictive value of motif neoepitopes in early and advanced stage NSCLC patients and to assess relevant clinical questions, we will perform analyses of patients in three separate clinical scenarios. As whole exome sequencing (WES) and transcriptomic data is now routinely obtained in our NSCLC patients as part of patients’ clinical care, we will analyze the presence and expression of genes harboring motif neoepitopes. We will evaluate baseline tumor biopsies from 75 early stage patients with an HLA-B44 allele who receive neoadjuvant chemotherapy plus PD-1 inhibition, correlating motif neoepitopes with pathologic complete response. Among 75 advanced stage patients with an HLA-B44 allele who are receiving single agent PD-1 inhibition and 75 additional patients being treated with chemotherapy plus PD-1 inhibition, we will correlate motif neoepitopes with progression of disease within 6 months of initiation of therapy. Together, these studies will provide a better understanding of the TME and other immunologic changes associated with the presence of motif neoepitopes. In addition, results could enable us to identify patients in whom evaluation of this marker of neoantigen presentation could be utilized to select patients with clinically relevant benefit in three separate clinical scenarios utilizing PD-1 inhibitor-based therapy. As a corollary, results could also identify populations of patients in whom other treatment strategies should be considered.

项目摘要 肺癌是美国和世界上癌症相关死亡的主要原因。我们最近 研究表明，程序性细胞死亡1（PD-1）抑制剂，这导致持久的反应，在少数 非小细胞肺癌（NSCLC）患者中，HLA-B结合荷电患者的疗效更高 其肿瘤具有导致我们指定为基序新表位的突变的口袋。基序 新表位在九聚体的第二位置具有氨基酸取代， 与野生型肽分离，得到的氨基酸具有与HLA-B结合口袋相反的电荷。 迄今为止，尚未探索基序新表位诱导的免疫学变化。我们提出了一个 全面评估潜在机制，重点关注HLA-B44超型等位基因患者 由于HLA-B44的流行率（约占人口的40%）和分布， 种族群体。我们将评估癌症基因组图谱（TCGA）中的HLA-B44样本，以探索 通过检测基因，在具有或不具有基序新表位的患者中的肿瘤微环境（TME） 表达和细胞组成的幻灯片审查和算法的基础上基因表达谱。我们将 评价来自有或无HLA-B44基序新表位的初治患者的手术标本， 通过多重免疫荧光（MIF）评估TME的空间特征。我们将评估多个部分 以鉴定与基序新表位最显著相关的生物标志物。我们将进一步 通过单细胞RNA-seq分析检查与基序新表位相关的TME的免疫结构。 阐明基序新表位在早期和晚期NSCLC患者中的预测价值， 评估相关的临床问题，我们将在三个不同的临床场景中对患者进行分析。作为 全外显子组测序（WES）和转录组学数据现在在我们的NSCLC患者中常规获得， 作为患者临床护理的一部分，我们将分析携带基序新表位的基因的存在和表达。 我们将评估75名携带HLA-B44等位基因的早期患者的基线肿瘤活检，这些患者接受 新辅助化疗加PD-1抑制，将基序新表位与病理学完全 反应在75例接受PD-1单药治疗的HLA-B44等位基因晚期患者中， 另外75名患者接受化疗加PD-1抑制治疗，我们将相关基序 在治疗开始后6个月内疾病进展的新表位。 总之，这些研究将提供对TME和其他免疫学变化的更好理解 与基序新表位的存在相关。此外，结果可以使我们能够识别患者， 对这种新抗原呈递标志物的评价可用于选择临床上 在三种不同的临床情况下，使用基于PD-1通道的治疗具有相关的益处。作为推论，结果 还可以确定应考虑其他治疗策略的患者人群。