Transfer Application - R01 CA223804 - Chemoimmunoprevention of EGFR-Driven Non-Small Cell Lung Cancer

项目总结 肺癌是全球癌症死亡的主要原因(1)。超过80%的肺癌是由 约50%的亚洲患者发生非小细胞肺癌(NSCLC)和EGFR内的激活突变 约20%的西方非小细胞肺癌患者(1)。与流行的观念相反，非小细胞肺癌中的EGFR突变 在男性和女性以及不吸烟者和不吸烟者中均可发生(1)。因此，以EGFR为靶点 非小细胞肺癌的发展将对控制该病产生重大影响。为了最大限度地发挥药效 预防措施在非小细胞肺癌中，最初的焦点将针对有癌前病变或 那些曾经接受过治疗的肺癌患者。预防糖尿病发展的两种有前景的治疗方法 NSCLC的干预措施旨在减缓肿瘤的发展(化学预防)或调节 肿瘤的免疫识别(免疫预防)。这一多PI计划将测试创新 肺癌的化学免疫预防策略--结合尤博士和王博士的经验 分别在化学预防和癌症免疫治疗方面的研究小组。之前在尤博士的工作 实验室已经证实维甲酸X受体(RXR)激动剂(贝沙罗汀和类似物UAB30)是有效的 肺癌小鼠模型中的化学预防药物(2，表1)。尤博士的团队也是第一个 针对EGFR驱动的多肽EGFR免疫预防疫苗显示显著效果 肺肿瘤发生(3)。王博士之前的工作已经建立了一种新的免疫检查点蛋白Vista作为一种 抗肿瘤免疫的关键调节剂(4-9)，这是一个重要贡献，因为免疫被阻断 检查点受体已被确定为癌症治疗的重大突破(10)。王博士的团队 研究表明，Vista阻断单抗可增强多种临床前小鼠的T细胞介导的肿瘤排斥反应 型号(4-9)。鉴于上述方法在控制肿瘤生长方面的既定效果， 我们假设化学免疫预防的组合方法将增强抗肿瘤免疫。 在肿瘤微环境(TME)内，这将抑制肺癌的进展和复发。三 为了检验这一假说，本文提出了具体的目标。目标1将研究RXR的免疫调节作用 激动剂在预防建立抑制T细胞活化的肿瘤微环境中的作用 患上肺癌。目的2将确定RXR激动剂联合治疗的预防效果 以及MHCII限制性EGFR多肽疫苗治疗EGFR驱动的肺癌进展。AIM 3将测试 阻断免疫检查点蛋白VistA和PD-L1与RXR协同作用的假说 激动剂/EGFR疫苗可防止获得性耐药和肿瘤复发。这项提议是非常重要的 意义重大，因为化学免疫预防有可能成为一种突破性的预防 肺癌的治疗方法。

PROJECT SUMMARY Lung cancer is the leading cause of cancer mortality worldwide (1). More than 80% of lung cancers consist of non-small cell lung cancer (NSCLC) and activating mutations within EGFR occur in ~50% of Asian patients and ~20% of Western patients with NSCLC (1). Contrary to prevailing notions, EGFR mutations in NSCLC occur in both males and females and in both nonsmokers and nonsmokers (1). Thus, targeting EGFR against development of NSCLC will have significant impact to control this disease. In order to maximize efficacy of preventive approaches in NSCLC, the initial focus will be directed toward patients with premalignant lesions or those with previously treated lung cancer. Two promising therapeutic approaches in preventing development of NSCLC are with interventions designed to attenuate tumor development (chemoprevention) or modulate immune recognition of tumor (immunoprevention). This multi-PI proposal will test innovative chemoimmunopreventive strategies for lung cancer, combining the expertise from Dr. You's and Dr. Wang's research groups in chemoprevention and cancer immunotherapy, respectively. Prior work in Dr. You's laboratory has established retinoid X receptor (RXR) agonists (bexarotene and an analog UAB30) as potent chemopreventive agents in mouse models of lung cancer (2, Table 1). Dr. You's group was also the first to demonstrate remarkable efficacy of an immunopreventive multi-peptide EGFR vaccine against EGFR-driven lung tumorigenesis (3). Dr. Wang's prior work has established a novel immune checkpoint protein VISTA as a critical regulator of anti-tumor immunity (4-9), an important contribution given that blockade of immune checkpoint receptors has been identified as a major breakthrough in cancer treatment (10). Dr. Wang's group has shown that VISTA-blocking mAb enhances T cell-mediated tumor rejection in multiple preclinical mouse models (4-9). Given the established efficacy of these aforementioned approaches in controlling tumor growth, we hypothesize that combinatorial approaches of chemoimmunoprevention will enhance anti-tumor immunity within the tumor microenvironment (TME), which will inhibit lung tumor progression and recurrence. Three specific aims are proposed to test this hypothesis. Aim 1 will investigate the immune regulatory role of RXR agonists in preventing establishment of a tumor microenvironment that suppresses T cell activation against developing lung cancer. Aim 2 will determine the preventive efficacy of combined treatment of RXR agonists and a MHCII-restricted EGFR multi-peptide vaccine on EGFR-driven lung tumor progression. Aim 3 will test the hypothesis that blocking immune checkpoint proteins VISTA and PD-L1 will synergize with RXR agonists/EGFR vaccine to prevent acquired resistance and tumor recurrence. This proposal is highly significant because of the potential of chemoimmunoprevention to become a breakthrough preventive approach for lung cancer.