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.

项目概要 最近，肺癌是美国和世界范围内癌症相关死亡的主要原因。 证明程序性细胞死亡 1 (PD-1) 抑制剂可在少数细胞中产生持久反应 非小细胞肺癌 (NSCLC) 患者，对 HLA-B 结合带电的患者具有更高的疗效 其肿瘤含有导致我们指定为基序新表位的突变。 新表位在九聚物的第二个位置有一个氨基酸取代，产生电荷变化 来自野生型肽，所得氨基酸具有与HLA-B结合口袋相反的电荷。 迄今为止，尚未探索由基序新表位引起的免疫学变化。 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%）以及 HLA-B44 在不同种族和人群中的分布 我们将评估癌症基因组图谱 (TCGA) 中的 HLA-B44 样本，以探索不同种族之间的差异。 通过检查基因来确定有或没有基序新表位的患者的肿瘤微环境（TME） 我们将通过幻灯片审查和基于基因表达谱的算法来确定表达和细胞组成。 评估来自未接受过治疗的患者（有或没有 HLA-B44 基序新表位）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切片。 我们将进一步从每个样本中鉴定与基序新表位最相关的生物标志物。 通过单细胞 RNA-seq 分析检查与基序新表位相关的 TME 的免疫环境。 阐明基序新表位对早期和晚期 NSCLC 患者的预测价值 评估相关的临床问题后，我们将在三个不同的临床场景中对患者进行分析。 现在我们的 NSCLC 患者中常规获得全外显子组测序 (WES) 和转录组数据 作为患者临床护理的一部分，我们将分析含有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，这些患者接受了 新辅助化疗加 PD-1 抑制，将基序新表位与病理完全相关 75 名携带 HLA-B44 等位基因的晚期患者正在接受单药 PD-1 治疗。 抑制和另外 75 名接受化疗加 PD-1 抑制治疗的患者，我们将关联主题 治疗开始后 6 个月内疾病进展的新表位。 总之，这些研究将有助于更好地了解 TME 和其他免疫学变化 此外，结果可以使我们识别患者。 可以利用这种新抗原呈递标志物的评估来选择临床上患有这种疾病的患者 作为推论，结果显示在三个不同的临床场景中使用基于 PD-1 抑制剂的疗法具有相关益处。 还可以确定应考虑其他治疗策略的患者群体。

项目成果

Accelerated Hypofractionated Chemoradiation Followed by Stereotactic Ablative Radiotherapy Boost for Locally Advanced, Unresectable Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial.

加速大分割化放疗后立体定向消融放疗加强治疗局部晚期不可切除的非小细胞肺癌：一项非随机对照试验。

• 发表时间: 2024-03-01
• 影响因子: 28.4
• 作者: Wu, Trudy C;Luterstein, Elaine;Neilsen, Beth K;Goldman, Jonathan W;Garon, Edward B;Lee, Jay M;Felix, Carol;Cao, Minsong;Tenn, Stephen E;Low, Daniel A;Kupelian, Patrick A;Steinberg, Michael L;Lee, Percy
• 通讯作者: Lee, Percy