BASE TITLE: PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM: PRECLINICAL EFFICACY AND ENDPOINT BIOMARKERS; TASK ORDER TITLE: EFGR AND KRAS VACCINE

基本标题：预防癌症临床前药物开发计划：临床前疗效和终点生物标志物；

• 批准号: 10269170
• 负责人: CHINTHALAPALLY V. RAO
• 金额: $ 89.09万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269170
• 关键词: Accounting; Acetyl-CoA C-Acetyltransferase; Alleles; Anti-Inflammatory Agents; Atherosclerosis; Attention; Binding; Biological Markers; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Patient; Cancer Vaccines; Cell Proliferation; Cell membrane; Cellular Immunity; Cessation of life; Cholesterol; Cholesterol Homeostasis; Clinical; Clinical Trials; Colon Carcinoma; Combined Modality Therapy; Data; Disease; Environment; Epidermal Growth Factor Receptor; Epitope spreading; Epitopes; Esterification; Exons; Goals; HLA-DR Antigens; Human; Immune; Immune response; Immunity; Immunocompetent; Immunotherapy; Individual; Isogeneic graft; KRAS2 gene; Lesion; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Modeling; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncogene Activation; Oncogenic; Oncoproteins; Patients; Peptide Vaccines; Peptides; Pharmaceutical Preparations; Point Mutation; Population; Populations at Risk; Preclinical Drug Development; Prevention; Preventive; Preventive vaccine; Program Development; Regimen; Resected; Safety; Smoker; Sterol O-Acyltransferase; T cell response; T-Cell Receptor; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Tumor Antigens; Vaccinated; Vaccination; Vaccines; Work; adaptive immune response; anti-tumor immune response; base; cancer recurrence; cytokine; cytotoxic CD8 T cells; design; disorder control; efficacy testing; high risk; immunogenicity; immunological intervention; immunological synapse formation; improved; inhibitor/antagonist; lung cancer prevention; lung tumorigenesis; mortality; mouse model; mutant; peptide vaccination; pre-clinical; preclinical efficacy; premalignant; prevent; recruit; relapse risk; response; small molecule inhibitor; tumor; tumor microenvironment; tumor progression

Lung cancer represents a significant clinical burden worldwide as the leading cause of cancer-related mortality, accounting for 19.4% of all cancer-related deaths. A key concept in lung cancer disease control is to prevent lung cancer progression in patients bearing premalignant lesions and to prevent lung cancer recurrence in those with previously treated lung cancer. Recent findings strongly support EGFR mutation testing in all patients with non-small cell lung cancer (NSCLC) and suggest that targeting EGFR for prevention will have significant impact in controlling this disease. The most common EGFR mutations (>90%) in lung cancer patients are deletions in exon 19 and/or point mutations in exon 21 (L858R). Mutations in KRAS, another major driver of lung cancer, are present in approximately 30% of lung cancer patients. KRAS mutations are also the major driver for several other human cancers including pancreatic and colon cancer, but efforts to target KRAS preventively or therapeutically have been unsuccessful. Since therapeutic efforts to inhibit RAS using small molecule inhibitors have been ineffective, peptide vaccination against tumor-specific mutant forms of RAS have received significant attention. Such immunological interventions are particularly important for high-risk individuals, for example former/current smokers and those with resected primary lung cancer at a high risk for relapse. Studies have shown that the Th1 helper cellular immunity is critical for immunotherapy-mediated cancer eradication. MHC II-restricted peptide vaccines elicit tumor antigen-specific Th1 immunity that orchestrates the reversal of immunesuppressive cytokine environment, recruitment of CD8+ Cytotoxic T lymphocytes (CTL), and escalation of the response via epitope spreading. Importantly, while MHC I–epitopes are highly HLA-DR restricted, MHC II epitopes can be designed to bind to multiple HLA-DR alleles and are thus applicable for broader populations of cancer patients. You et al designed MHC II-restricted multi-peptide vaccines against EGFR and KRAS, and showed that these vaccines can significantly (~80%) decrease oncoprotein-driven lung tumorigenesis in corresponding transgenic murine models of lung cancer when vaccinated before oncoprotein induction. However, diminished efficacy was observed when the vaccines were given two weeks after the oncoprotein induction, suggesting the presence of immunosuppressive mechanisms in the tumor microenvironment soon after the oncogene activation. High-risk individuals may already have active oncogenic mutations long before the onset of lung tumorigenesis, which could contribute significantly to an immune suppressive microenvironment, thereby hampering the vaccine-induced immune responses. Therefore, testing efficacy of a vaccine in combination with agents that can inhibit the immune suppressive microenvironment is highly significant. The Acetyl-CoA acetyltransferase (ACAT) inhibitor, Avasimibe (AVA), is an anti-inflammatory drug that has a good safety profile in clinical trials for treating atherosclerosis. Recent studies show that AVA promotes anti-tumor immune responses by increasing the effector function of tumor specific CD8+ cytotoxic T cells. Activated CD8+ T cells undergo alterations in cholesterol metabolism and synthesis to support rapid cell proliferation. AVA inhibits cholesterol esterification, upregulates plasma membrane cholesterol levels, enhances T-cell receptor (TCR) clustering, and promotes formation of the immunological synapse in CD8+ T cells. Recent work by You et al. demonstrated that the combination of AVA and their multipeptide KRAS vaccine could elicit improved anti-tumor efficacy both in a syngraft and transgenic mouse models of lung cancer, where KRAS activation was initiated long before vaccination. Based on these data, it is conceivable that chemo-immunoprevention strategies such as combination of AVA and cancer vaccines may be a rational approach to lung cancer prevention when the vaccine is administrated in the presence of subclinical disease. The combination is postulated to promote concurrent CD4+ and CD8+ T cell responses thereby providing an enhanced benefit to improve anti-tumor adaptive immune responses.

肺癌作为癌症相关死亡的主要原因，在全世界范围内构成了重大的临床负担，占所有癌症相关死亡的 19.4%。 肺癌疾病控制的一个关键概念是预防患有癌前病变的患者的肺癌进展，并预防既往接受过治疗的肺癌患者的肺癌复发。 最近的研究结果强烈支持对所有非小细胞肺癌 (NSCLC) 患者进行 EGFR 突变检测，并表明针对 EGFR 进行预防将对控制这种疾病产生重大影响。 肺癌患者中最常见的 EGFR 突变 (>90%) 是外显子 19 的缺失和/或外显子 21 (L858R) 的点突变。 KRAS 突变是肺癌的另一个主要驱动因素，约 30% 的肺癌患者存在 KRAS 突变。 KRAS 突变也是其他几种人类癌症（包括胰腺癌和结肠癌）的主要驱动因素，但针对 KRAS 进行预防或治疗的努力尚未成功。 由于使用小分子抑制剂抑制 RAS 的治疗努力无效，因此针对肿瘤特异性 RAS 突变形式的肽疫苗接种受到了广泛关注。 这种免疫干预措施对于高危个体尤其重要，例如以前/现在吸烟者和原发性肺癌切除后复发风险较高的人。 研究表明，Th1 辅助细胞免疫对于免疫疗法介导的癌症根除至关重要。 MHC II 限制性肽疫苗可引发肿瘤抗原特异性 Th1 免疫，从而协调免疫抑制细胞因子环境的逆转、招募 CD8+ 细胞毒性 T 淋巴细胞 (CTL)，并通过表位扩散增强反应。 重要的是，虽然 MHC I 表位受到 HLA-DR 的高度限制，但 MHC II 表位可以设计为与多个 HLA-DR 等位基因结合，因此适用于更广泛的癌症患者群体。 You等人设计了针对EGFR和KRAS的MHC II限制性多肽疫苗，并表明，在癌蛋白诱导前接种疫苗时，这些疫苗可以显着（~80%）减少相应转基因小鼠肺癌模型中癌蛋白驱动的肺部肿瘤发生。 然而，在癌蛋白诱导两周后接种疫苗时，观察到功效减弱，这表明癌基因激活后不久，肿瘤微环境中就存在免疫抑制机制。 高风险个体可能早在肺部肿瘤发生之前就已经具有活跃的致癌突变，这可能对免疫抑制微环境产生重大影响，从而阻碍疫苗诱导的免疫反应。 因此，测试疫苗与可抑制免疫抑制微环境的药物组合的功效非常重要。 乙酰辅酶A乙酰转移酶（ACAT）抑制剂阿瓦西米贝（AVA）是一种抗炎药，在治疗动脉粥样硬化的临床试验中具有良好的安全性。 最近的研究表明，AVA 通过增加肿瘤特异性 CD8+ 细胞毒性 T 细胞的效应功能来促进抗肿瘤免疫反应。 激活的 CD8+ T 细胞会改变胆固醇代谢和合成，以支持细胞快速增殖。 AVA 抑制胆固醇酯化，上调质膜胆固醇水平，增强 T 细胞受体 (TCR) 聚集，并促进 CD8+ T 细胞中免疫突触的形成。 You 等人最近的工作。证明 AVA 与其多肽 KRAS 疫苗的组合可以在肺癌同种移植和转基因小鼠模型中提高抗肿瘤功效，其中 KRAS 激活早在疫苗接种之前就已开始。 基于这些数据，可以想象，在存在亚临床疾病的情况下接种疫苗时，化学免疫预防策略（例如 AVA 和癌症疫苗的组合）可能是预防肺癌的合理方法。 该组合被认为可以促进同时发生的 CD4+ 和 CD8+ T 细胞反应，从而增强抗肿瘤适应性免疫反应的效果。