PREVENT EFFICACY POOL: PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM

点击翻译按钮获取中文摘要

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.