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.

项目摘要/摘要 致癌性KRASG12C（kg12c）突变基于约13％的非斑点非小细胞肺的发展。 癌症（NSCLC）每年在美国占10,000人死亡，潜力，选择性和 KG12C癌蛋白的临床活性共价抑制剂代表了最令人兴奋的进步之一 在有针对性的癌症疗法领域，但策略旨在规避自适应抗性和 迫切需要提高对KG12C抑制剂的耐用性 患者的结果。除了它们的肿瘤细胞内膜作用外，KG12C抑制剂还原肿瘤 临床前模型中的免疫微环境，并与抗PD-1治疗协同促进长期 肿瘤回归和免疫记忆。基于KG12C抑制剂触发免疫的机制 KG12C NSCLC中的途径激活知之甚少。此外，KG12C的最佳组合 具有护理标准（SOC）一线NSCLC全身疗法在内的抑制剂（包括白金双重） 化学疗法，PD-1抑制剂单一疗法和化学免疫疗法，以最大化抗肿瘤免疫力 尚未建立。此外，STK11/LKB1，KEAP1，KEAP1，COPURRING基因组改变的影响 TP53和RBM10 - 塑造Kras突变NSCLC的免疫膜片，并修改其对PD-的反应 1轴封锁 - 基于KG12C抑制剂治疗的临床效率和免疫后遗症 尚未系统地检查组合。根据我们的初步发现和以前的工作 假设：1。免疫原性死亡的诱导有助于KG12C抑制剂触发的免疫途径 KG12C NSCLC中的激活； 2。kg12c抑制剂暴露的免疫敏化作用，可以进一步增强 加入化学疗法和/或免疫检查点抑制剂（ICI）； 3。共发生的基因组改变 在KG12C中影响KG12C抑制剂单和联合疗法的临床和免疫反应 NSCLC。在AIM 1中，我们将剖析KG12C抑制剂介导的免疫的机制和分子决定剂 KG12C NSCLC中的敏化。在AIM 2中，我们将评估协同KG12C抑制剂与标准的相互作用 护理一线全身疗法（包括铂 - 双重化疗，PD-（L）1抑制剂单一疗法和 KG12C突变NSCLC的免疫能力小鼠模型中的化学免疫疗法）。在AIM 3中，我们将验证 治疗诱导的KG12C NSCLC免疫环境的变化在全肿瘤和单细胞分辨率下的变化 使用手术切除的KG12C NSCLC患者的临床样本，这些KG12C NSCLC接受了新辅助治疗 AMG 510与研究者引起的2期临床试验中的铂双化疗结合使用。 临床意义：这项工作将产生有关机制的新见解，并确定免疫途径 响应KG12C抑制剂单和联合疗法的激活，将有助于发展 个性化的共同限制了联合治疗策略，旨在最大化免疫 从KG12C抑制剂中敏感的潜力和长期临床益处。