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率的主要原因。 KRAS是肺腺癌患者中最常见的癌基因，而EGFR突变发生在47.9％的非小细胞肺癌（NSCLC）和19.2％的西方患者中。此外，在NSCLC的40-89％中已经确定了EGFR的表达。这些发现表明，将这些突变靶向预防可能会对控制这种疾病产生重大影响。肺癌疾病控制的一个关键概念是防止恶性病变患者的肺癌进展，并防止先前治疗的肺癌患者的肺癌复发。 KRAS和EGFR突变都很容易在侵入性肺部病变中发现，致癌性KRAS或EGFR突变与患侵袭性和转移性肺癌的风险增加有关。研究表明，TH1辅助细胞免疫疗法对于免疫疗法介导的癌症辐射至关重要。 MHC II限制的肽疫苗引起肿瘤抗原特异性TH1免疫组织化学，该组织策划了免疫抑制环境的逆转。针对EGFR和KRAS的MHC II限制的多肽疫苗表明，当在诱导癌蛋白活性之前接种疫苗时，这些疫苗在肺癌的转基因鼠模型中可以显着（〜80％）减少癌蛋白驱动的肺肿瘤发生。然而，当疫苗诱导后两周给予疫苗时，观察到效率的降低，这表明癌基因激活后不久，肿瘤微环境中存在免疫抑制机制。同样，高危个体可能已经在明显的肺肿瘤发生之前就已经具有活跃的致癌突变，这可能会对免疫抑制的微环境产生重大贡献，从而阻碍疫苗诱导的免疫调查。因此，疫苗与可以抑制免疫抑制微环境的药物结合的测试效率非常关键。 CA-170是一种新型的三肽蛋白vista的小分子拮抗剂（V域Ig的Ig抑制T细胞激活）具有出色的口服生物利用度，相对短的半寿命，并且可以依赖性地依赖性地依赖性地增强其在其能力上呈现型淋巴细胞的增殖。临床前毒理学研究中的毒性特征。在最近针对晚期实体瘤或淋巴瘤患者的临床研究中，CA-170具有良好的安全性，半衰期相对较短，并且通过肿瘤回归实现了免疫调节作用。因此，抗原特异性的多肽疫苗接种和免疫切解点的结合应增加抗原特异性T细胞活化。先前的动物研究表明，随着掺入气溶胶的癌症预防药物可直接输送到肺部，可提高效率，以预防肺癌，同时减少由于系统性暴露而减少不良反应。这是雾化的CA-170可以显着提高KRAS或EGFR疫苗抑制KRAS/EGFR驱动癌的效率。该项目的总体目的是测试与KRAS或EGFR多肽疫苗和雾化CA-170的组合治疗是否会提高KRAS或EGFR疫苗的免疫预防效率，以针对由KRAS或EGFR突变驱动的转基因动物中的肺肿瘤进展，并评估免疫学反应，并评估免疫学反应，并评估均质效率。