PREVENT EFFICACY POOL: PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM

预防功效池：预防癌症临床前药物开发计划

基本信息

批准号：
10411703
负责人：
CHINTHALAPALLY RAO
金额：
$ 91.15万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-24 至 2023-11-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411703
关键词：
Adverse effects Aerosols Animal Model Animals Antigens Asia Biological Availability Cancer Etiology Cellular Immunity Clinical Research Combined Vaccines Disease Dose Environment Epidermal Growth Factor Receptor Genetically Engineered Mouse Goals Half-Life Immune Immune response Immunity Immunotherapy Individual Inhalation KRAS oncogenesis KRAS2 gene Lesion Lung Lung Adenocarcinoma Lung Neoplasms Lymphoma Malignant Neoplasms Malignant neoplasm of lung Mediating Modeling Mus Mutation Non-Small-Cell Lung Carcinoma Oncogene Activation Oncogenes Oncogenic Oncoproteins Oral Patients Peptide Vaccines Preclinical Drug Development Prevention Program Development Proteins Regimen Risk Safety Solid Neoplasm Suppressor-Effector T-Lymphocytes T-Cell Activation T-Lymphocyte Testing Toxic effect Toxicology Transgenic Animals Transgenic Organisms Tumor Antigens Vaccinated Vaccines Wild Type Mouse aerosolized antigen-specific T cells cancer prevention cancer recurrence carcinogenesis disorder control efficacy testing high risk immune checkpoint immune checkpoint blockade improved in vivo lung tumorigenesis mortality mouse model novel peptide vaccination pre-clinical premalignant prevent small molecule tumor tumor microenvironment tumor progression vaccine efficacy

项目摘要

Lung cancer is the leading cause of cancer mortality worldwide. KRAS is the most common oncogene in lung adenocarcinoma patients while EGFR mutations occur in 47.9% of Asia-Pacific patients with non-small cell lung cancer (NSCLC) and 19.2% of Western patients. Furthermore, EGFR over expression has been identified in 40–89% of NSCLC. These findings suggest that targeting these mutations for prevention may have significant impact in controlling this disease. A key concept in lung cancer disease control is to prevent lung cancer progression in patients with pre-malignant lesions and to prevent lung cancer recurrence in those with previously treated lung cancer. Both KRAS and EGFR mutations are readily found in pre-invasive lung lesions, and oncogenic KRAS or EGFR mutations are associated with an increased risk of developing invasive and metastatic lung cancer. 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 the immune suppressive environment. MHC II-restricted multi-peptide vaccines against EGFR and KRAS have shown that these vaccines can significantly (~80%) decrease oncoprotein-driven lung tumorigenesis in transgenic murine models of lung cancer when vaccinated before the induction of oncoprotein activity. 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. Similarly, high-risk individuals may already have active oncogenic mutations long before the onset of overt lung tumorigenesis, which could contribute significantly to the 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 critical. CA-170, a novel tripeptide small molecule antagonist of the immune checkpoint protein VISTA (V-domain Ig suppressor of T-cell activation) has excellent oral bioavailability, a relatively short half-life, and it can dose-dependently enhance the proliferation of T lymphocytes due to its ability to inhibit VISTA In syngeneic murine tumor models, CA-170 also showed a highly favorable toxicity profile in preclinical toxicology studies. In recent clinical studies in patients with advanced solid tumors or lymphomas, CA-170 had a favorable safety profile with a relatively short half-life and demonstrated immune-modulating effects, accompanied by tumor regression. Therefore, a combination of an antigen-specific multi-peptide vaccination and immune checkpoint blockade should increase antigen-specific T cell activation. Previous animal studies have demonstrated that cancer prevention agents delivered directly to the lungs as inhaled aerosols provide enhanced efficacy to prevent lung cancer while reducing adverse effects due to reduced systemic exposure. Thus, aerosolized CA-170 may significantly enhance the efficacy of the KRAS or EGFR vaccine to inhibit KRAS/EGFR driven carcinogenesis. The overall goal of the project is to test whether combination treatment with KRAS or EGFR multi-peptide vaccines and aerosolized CA-170 will improve immunopreventive efficacy of KRAS or EGFR vaccine against lung tumor progression in transgenic animal models driven by KRAS or EGFR mutations, and assess immunologic responses that correlate vaccine efficacy.

肺癌是全球癌症死亡的主要原因。KRAS 是肺腺癌患者中最常见的癌基因，而 EGFR 突变发生在 47.9% 的亚太非小细胞肺癌 (NSCLC) 患者和 19.2% 的西方患者中。此外，40-89% 的 NSCLC 中已发现 EGFR 过度表达，这些发现表明针对这些突变进行预防可能对控制这种疾病产生重大影响。肺癌疾病控制是指预防癌前病变患者的肺癌进展，以及预防既往治疗过的肺癌患者的肺癌复发。 KRAS 和 EGFR 突变在浸润前肺部病变中很容易发现，致癌性 KRAS 或 EGFR 突变与发生浸润性和转移性肺癌的风险增加有关。研究表明，Th1 辅助细胞免疫对于免疫治疗介导的至关重要。 MHC II 限制性肽疫苗可引发肿瘤抗原特异性 Th1 免疫，从而协调逆转针对 EGFR 的免疫抑制环境。然而，KRAS 表明，在肺癌转基因小鼠模型中，在诱导癌蛋白活性之前接种疫苗，这些疫苗可以显着（约 80%）减少癌蛋白驱动的肺部肿瘤发生，而在接种疫苗两周后接种疫苗时，观察到效果减弱。癌蛋白诱导，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。同样，高危个体可能在明显的肺部肿瘤发生之前很久就已经存在活跃的致癌突变。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关键。 CA-170是一种新型免疫检查点蛋白VISTA（T细胞激活V域Ig抑制因子）的三肽小分子拮抗剂，具有优异的口服生物利用度、相对较短的半衰期，并能剂量依赖性地增强细胞增殖。 T 淋巴细胞由于具有抑制 VISTA 的能力，在同基因小鼠肿瘤模型中，CA-170 在临床前毒理学研究中也显示出非常有利的毒性特征。对于淋巴瘤，CA-170 具有良好的安全性，半衰期相对较短，并具有免疫调节作用，并伴有肿瘤消退，因此，抗原特异性多肽疫苗接种和免疫检查点阻断的结合应该会增加抗原特异性。特异性 T 细胞激活。先前的动物研究表明，以吸入气雾剂的形式直接输送到肺部的癌症预防剂可增强预防肺癌的功效，同时减少由于全身暴露而产生的不良反应，因此，雾化的 CA-170 可能会增强 KRAS 或 EGFR 疫苗的功效。该项目的总体目标是测试 KRAS 或 EGFR 多肽疫苗与雾化 CA-170 的联合治疗是否会改善。在 KRAS 或 EGFR 突变驱动的转基因动物模型中，KRAS 或 EGFR 疫苗对肺肿瘤进展的免疫预防功效，并评估与疫苗功效相关的免疫反应。