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 肺癌是美国和世界癌症相关死亡的主要原因。我们最近 证明了程序性细胞死亡1（PD-1）抑制剂，这导致少数族裔的反应 非小细胞肺癌（NSCLC）患者，在带电HLA-B结合的患者中具有更高的效率 肿瘤携带突变的口袋导致我们设计为基序的垂直群。主题 Neoeppitopes在非准备的第二个位置的氨基酸取代 从野生型肽中产生的氨基酸与HLA-B结合口袋相反。 迄今为止，尚未探讨由基序培养基引起的免疫学变化。我们提出了一个 对基本机制的全面评估，重点是HLA-B44超级等级等位基因的患者 由于普遍存在（约占人口的40％）和HLA-B44在种族中的分布 族裔。我们将评估癌症基因组图集（TCGA）中的HLA-B44样品，以探讨 通过检查基因，有或没有基序的Neoepitopes患者的肿瘤微环境（TME） 基于基因表达谱的幻灯片回顾和算法的表达和细胞组成。我们将 评估患有或没有HLA-B44基序的幼稚患者的手术标本和 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 从每个标本中识别出与基序垂体最显着相关的生物标志物。我们将进一步 通过单细胞RNA-Seq分析检查与基序neoepopes相关的TME的免疫膜片。 阐明在早期和晚期NSCLC患者中基序垂体的预测价值， 评估相关的临床问题，我们将在三种不同的临床情况下对患者进行分析。 现在，我们的NSCLC患者常规获得整个外显子组测序（WES）和转录组数据 在患者的一部分临床护理中，我们将分析具有基序的基因的存在和表达。 我们将评估来自75名HLA-B44等位基因的75例早期阶段患者的基线肿瘤活检 新辅助化学疗法加上PD-1抑制作用，将基序新垂体与病理完整相关 回复。在75名HLA-B44等位基因的高级阶段患者中，他们正在接受单位代理PD-1 抑制作用和75名接受化学疗法和PD-1抑制治疗的其他患者，我们将相关 在开始治疗后的6个月内，有疾病进展。 这些研究将共同​​了解TME和其他免疫学变化 与基序的存在有关。此外，结果可以使我们能够确定 可以使用对新抗原表现标记的评估来选择临床上的患者 利用基于PD-1抑制剂的治疗的三种单独的临床方案中的相关益处。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。