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

项目摘要 肺癌是全球癌症死亡率的主要原因（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NSCLC患者（1）。与流行的观念相反，NSCLC中的EGFR突变 发生在男性和女性以及非吸烟者和非吸烟者（1）。因此，靶向EGFR NSCLC的发展将对控制这种疾病产生重大影响。为了最大限度地发挥 NSCLC的预防方法，最初的重点将针对癌前病变患者，或 既往接受过肺癌治疗的患者。两种有前途的治疗方法，以防止发展的 NSCLC的干预措施旨在减弱肿瘤发展（化学预防）或调节 肿瘤免疫识别（免疫预防）。这个多PI提案将测试创新 肺癌的化学免疫预防策略，结合尤博士和王博士的专业知识， 化学预防和癌症免疫治疗的研究小组。在Dr. You's的工作 一个实验室已经建立了类维生素A X受体（RXR）激动剂（贝沙罗汀和类似物UAB 30）作为有效的 在肺癌小鼠模型中，使用化学预防剂（2，表1）。尤博士的团队也是第一个 证实了免疫预防性多肽EGFR疫苗对EGFR驱动的 肺肿瘤发生（3）。王博士先前的工作已经建立了一种新的免疫检查点蛋白VISTA， 抗肿瘤免疫的关键调节剂（4-9），鉴于免疫阻断的重要贡献 检查点受体已被确定为癌症治疗的重大突破（10）。王博士的小组 已经显示，VISTA阻断mAb在多个临床前小鼠中增强T细胞介导的肿瘤排斥 模型（4-9）。鉴于上述这些方法在控制肿瘤生长方面的既定功效， 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，这将抑制肺肿瘤的进展和复发。三 提出了具体目标来检验这一假设。目的1探讨RXR的免疫调节作用 激动剂在防止建立抑制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 和MHCII限制性EGFR多肽疫苗对EGFR驱动的肺肿瘤进展的影响。目标3将测试 阻断免疫检查点蛋白VISTA和PD-L1将与RXR协同作用的假设 激动剂/EGFR疫苗，以防止获得性耐药性和肿瘤复发。这一建议高度 重要的是，化学免疫预防有可能成为一种突破性的预防措施， 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.