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

项目总结/摘要 致癌性KRASG 12 C（KG 12 C）突变支持约13%的非鳞状非小细胞肺 在美国，每年约有10，000人死于非小细胞肺癌。 具有临床活性的KG 12 C癌蛋白共价抑制剂代表了最令人兴奋的最新进展之一 在靶向癌症治疗领域，避免适应性耐药性发展的策略， 迫切需要改善对KG 12 C抑制剂的个体应答的持久性，以改变临床 患者的结果。除了它们的肿瘤细胞内在效应之外，KG 12 C抑制剂修复肿瘤 并与抗PD-1治疗协同作用以促进长期 肿瘤消退和免疫记忆。支持KG 12 C旁路触发免疫的机制 KG 12 C NSCLC中的信号通路激活知之甚少。此外，KG 12 C的最佳组合 抑制剂与标准治疗（SOC）一线NSCLC全身性治疗（包括铂双联） 化疗、PD-1抑制剂单药治疗和化学免疫治疗，以最大限度地提高抗肿瘤免疫力 尚未建立。此外，STK 11/LKB 1，KEAP 1， TP 53和RBM 10-塑造KRAS突变型NSCLC的免疫结构并改变其对PD的反应- 1轴阻滞-基于KG 12 C通道的治疗性药物的临床疗效和免疫学后遗症 这些组合尚未得到系统的研究。根据我们的初步研究结果和以前的工作， 假设：1.诱导免疫原性细胞死亡有助于KG 12 C介导的免疫途径 KG 12 C NSCLC中的活化; 2. KG 12 C抑制剂表现出可进一步增强的免疫增敏作用 加入化疗和/或免疫检查点抑制剂（ICI）; 3.共同发生的基因组改变 影响对KG 12 C抑制剂单药和联合治疗KG 12 C的临床和免疫应答 NSCLC。在目的1中，我们将剖析KG 12 C靶介导的免疫应答的机制和分子决定因素。 在KG 12 C NSCLC中的致敏作用。在目标2中，我们将评估协同KG 12 C抑制剂与标准药物的相互作用。 一线全身治疗（包括铂类药物双联化疗、PD-（L）1抑制剂单药治疗和 化学免疫疗法）在免疫活性小鼠模型的KG 12 C突变型NSCLC中的应用。在目标3中，我们将验证 在全肿瘤和单细胞分辨率下治疗诱导的KG 12 C NSCLC免疫结构变化 使用来自手术切除的KG 12 C NSCLC患者的临床样本， AMG 510联合铂类药物双联化疗在一项化疗药物启动的II期临床试验中的应用。 临床意义：这项工作将对免疫途径的机制和决定因素产生新的见解 KG 12 C抑制剂单药治疗和联合治疗后， 个性化的共突变-定制的组合治疗策略，旨在最大限度地提高免疫- KG 12 C抑制剂的致敏潜力和长期临床获益。

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.