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

项目摘要/摘要 致癌性KRASG12C(KG12C)突变支持~13%的非鳞状非小细胞肺的发生 癌症(NSCLC)，在美国每年造成约10,000人死亡。有效、选择性和 临床上具有活性的KG12C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，然而，规避适应性耐药和 提高个体对KG12C抑制剂反应的持久性是转变临床急需的 患者的结果。除了其对肿瘤细胞的内在作用外，KG12C抑制剂还能对肿瘤进行修复 临床前模型中的免疫微环境及其与抗PD-1治疗的协同促进长期疗效 肿瘤退化和免疫记忆。KG12C抑制剂触发免疫的机制 KG12C非小细胞肺癌中的通路激活尚不清楚。此外，KG12C的最佳组合 标准护理(SOC)一线非小细胞肺癌系统治疗的抑制剂，包括铂-双联 化疗、PD-1抑制剂单一治疗和化学免疫治疗以最大限度地提高抗肿瘤免疫 还没有建立起来。此外，STK11/LKB1、KEAP1、 TP53和RBM10-塑造KRAS突变体NSCLC的免疫环境并改变其对PD的反应- 1轴阻断--KG12C抑制剂治疗的临床疗效及免疫后遗症 还没有对组合进行系统的研究。基于我们的初步发现和之前的工作，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非小细胞肺癌中的激活；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.共同发生的基因组改变 KG12C抑制剂单用和联合治疗对KG12C临床和免疫学反应的影响 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非小细胞肺癌的敏化作用。在目标2中，我们将评估KG12C抑制剂与标准的 CARE一线系统疗法(包括铂双联化疗、PD-(L)1抑制剂单一疗法和 在KG12C突变非小细胞肺癌免疫活性小鼠模型中)。在目标3中，我们将验证 治疗诱导的KG12C非小细胞肺癌全瘤和单细胞分辨免疫结构的变化 手术切除的KG12C非小细胞肺癌患者接受新辅助治疗的临床标本 AMG 510联合铂双联化疗在研究人员发起的第二阶段临床试验中。 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 KG12C抑制剂单一或联合治疗后的激活，并将促进 个性化共突变-量身定制的组合治疗策略，旨在最大化免疫- KG12C抑制剂的增敏潜力和长期临床益处。

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.