Understanding and harnessing immune-modulatory effects of covalent KRASG12C inhibitors in KRASG12C-mutant non-small cell lung cancer

了解和利用共价 KRASG12C 抑制剂对 KRASG12C 突变非小细胞肺癌的免疫调节作用

• 批准号: 10478950
• 负责人: Ferdinandos Skoulidis
• 金额: $ 37.06万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478950
• 关键词: Animal Model; Autologous; Biological; Biopsy; Cancer cell line; Cell Death Induction; Cells; Cessation of life; Cisplatin; Clinical; Combined Modality Therapy; DNA Sequence Alteration; Data; Data Set; Development; Exhibits; Foundations; Genetic Engineering; Genetically Engineered Mouse; Genomics; Heterogeneity; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune signaling; Immunization; Immuno-Chemotherapy; Immunocompetent; Immunologic Memory; Immunologics; Immunology procedure; Immunotherapy; KRAS2 gene; Mediating; Medicine; Molecular; Mus; Mutation; Neoadjuvant Therapy; Non-Small-Cell Lung Carcinoma; Oncogenic; Oncoproteins; Operative Surgical Procedures; PD-1 inhibitors; Pathway interactions; Patient-Focused Outcomes; Patients; Pemetrexed; Phase II Clinical Trials; Plasma; Platinum; Population; Pre-Clinical Model; Property; Research Personnel; Resected; Resistance; Resolution; Resources; STK11 gene; Sampling; Shapes; Specimen; Systemic Therapy; T memory cell; TP53 gene; Therapeutic; Tumor Immunity; Tumor Suppressor Genes; Work; anti-PD1 therapy; anti-tumor immune response; base; chemotherapy; clinical efficacy; clinically significant; early phase clinical trial; experimental study; immunogenic cell death; improved; individual response; inhibitor; insight; mouse model; mutant; neoplastic cell; novel; objective response rate; programmed cell death ligand 1; programmed cell death protein 1; response; standard of care; targeted cancer therapy; tumor; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Oncogenic KRASG12C (KG12C) mutations underpin the development of ~13% of non-squamous non-small cell lung cancer (NSCLC) and account for ~10,000 deaths annually in the U.S. The development of potent, selective and clinically active covalent inhibitors of the KG12C oncoprotein represents one of the most exciting recent advances in the field of targeted cancer therapy, yet strategies to circumvent the development of adaptive resistance and improve the durability of individual responses to KG12C inhibitors are urgently needed in order to transform clinical outcomes for patients. In addition to their tumor cell-intrinsic effects, KG12C inhibitors recondition the tumor immune microenvironment in preclinical models and synergize with anti-PD-1 therapy to promote long-term tumor regressions and immunological memory. The mechanisms that underpin KG12C inhibitor-triggered immune pathway activation in KG12C NSCLC are poorly understood. Furthermore, the optimal combinations of KG12C inhibitors with standard of care (SOC) first-line NSCLC systemic therapies including platinum-doublet chemotherapy, PD-1 inhibitor monotherapy and chemo-immunotherapy in order to maximize antitumor immunity have not been established. Furthermore, the impact of co-occurring genomic alterations in STK11/LKB1, KEAP1, TP53 and RBM10 – that shape the immune contexture of KRAS-mutant NSCLC and modify its response to PD- 1 axis blockade – on the clinical efficacy and immunological sequelae of KG12C inhibitor-based therapeutic combinations has not been systematically examined. Based on our preliminary findings and previous work we hypothesize that: 1. Induction of immunogenic cell death contributes to KG12C inhibitor-triggered immune pathway activation in KG12C NSCLC; 2. KG12C inhibitors exhibit immune-sensitizing effects that can be further enhanced with the addition of chemotherapy and/or immune checkpoint inhibitors (ICI); 3. Co-occurring genomic alterations impact both clinical and immunological responses to KG12C inhibitor mono- and combination therapy in KG12C NSCLC. In Aim 1, we will dissect mechanisms and molecular determinants of KG12C inhibitor-mediated immune sensitization in KG12C NSCLC. In Aim 2, we will evaluate synergistic KG12C inhibitor interactions with standard of care first-line systemic therapies (including platinum-doublet chemotherapy, PD-(L)1 inhibitor monotherapy and chemo-immunotherapy) in immune-competent mouse models of KG12C-mutant NSCLC. In Aim 3, we will validate treatment-induced changes in the KG12C NSCLC immune contexture at whole-tumor and single-cell resolution using clinical samples from patients with surgically resected KG12C NSCLC who were treated with neo-adjuvant AMG 510 in combination with platinum-doublet chemotherapy in an investigator-initiated phase 2 clinical trial. Clinical significance: This work will yield fresh insights into mechanisms and determinants of immune pathway activation in response to KG12C inhibitor mono- and combination therapy and will facilitate the development of personalized co-mutation-tailored combination therapeutic strategies that aim to maximize the immune- sensitizing potential and long-term clinical benefit from KG12C inhibitors.

项目概要/摘要 致癌 KRASG12C (KG12C) 突变支撑约 13% 的非鳞状非小细胞肺的发育 癌症 (NSCLC) 每年导致美国约 10,000 人死亡。 KG12C 癌蛋白的临床活性共价抑制剂代表了最新最令人兴奋的进展之一 在靶向癌症治疗领域，还存在规避适应性耐药性和 为了改变临床现状，迫切需要提高个体对 KG12C 抑制剂反应的持久性 患者的结果。除了其肿瘤细胞内在作用外，KG12C 抑制剂还可以修复肿瘤 临床前模型中的免疫微环境并与抗PD-1疗法协同作用以促进长期 肿瘤消退和免疫记忆。 KG12C 抑制剂触发免疫的基础机制 KG12C NSCLC 中的通路激活尚不清楚。此外，KG12C的最佳组合 抑制剂与标准护理 (SOC) 一线 NSCLC 全身疗法，包括铂类双联疗法 化疗、PD-1抑制剂单一疗法和化学免疫疗法，以最大限度地提高抗肿瘤免疫力 尚未成立。此外，STK11/LKB1、KEAP1 中同时发生的基因组改变的影响， TP53 和 RBM10 – 塑造 KRAS 突变 NSCLC 的免疫环境并改变其对 PD 的反应 1 轴阻断——基于 KG12C 抑制剂的治疗的临床疗效和免疫学后遗症 组合尚未经过系统研究。根据我们的初步调查结果和之前的工作，我们 假设： 1. 诱导免疫原性细胞死亡有助于 KG12C 抑制剂触发的免疫途径 KG12C NSCLC 中的激活； 2. KG12C抑制剂表现出可进一步增强的免疫增敏作用 添加化疗和/或免疫检查点抑制剂（ICI）； 3.同时发生的基因组改变 影响 KG12C 抑制剂单药和联合治疗的临床和免疫反应 非小细胞肺癌。在目标 1 中，我们将剖析 KG12C 抑制剂介导的免疫的机制和分子决定因素 KG12C NSCLC 的致敏作用。在目标 2 中，我们将评估协同 KG12C 抑制剂的相互作用与标准 一线全身治疗（包括铂类双药化疗、PD-(L)1抑制剂单药治疗和 KG12C 突变 NSCLC 的免疫活性小鼠模型中的化学免疫疗法）。在目标 3 中，我们将验证 在全肿瘤和单细胞分辨率下治疗引起的 KG12C NSCLC 免疫环境变化 使用手术切除的 KG12C NSCLC 患者的临床样本，并接受新辅助治疗 在一项由研究者发起的 2 期临床试验中，AMG 510 与铂类双药化疗相结合。 临床意义：这项工作将为免疫途径的机制和决定因素带来新的见解 KG12C 抑制剂单药和联合疗法的激活，将促进 个性化共突变定制的联合治疗策略，旨在最大限度地提高免疫 KG12C 抑制剂的增敏潜力和长期临床益处。