Abstract 4097: LNP-mRNA neoantigen vaccines to intercept progression of pre-invasive to invasive lung adenocarcinoma

Abstract The widespread use of chest computed tomography in lung cancer screening has led to the detection of ground-glass opacity (GGO) nodules, which typically harbor pre-invasive or minimally invasive adenocarcinoma and 20-40% of GGO nodules progress to invasive lung adenocarcinoma within 4 years. Lack of approved treatments to intercept disease progression has imposed challenges in the clinical management of patients with GGOs. Previous studies showed that GGO nodules have substantially lower rates of HLA deletions than invasive/metastatic lung cancer, suggesting that GGO nodules constitute a critical window of vulnerability for immune interception. We therefore sought to identify the most immunogenic and cytotoxic neoantigens in patients with GGO nodules and to develop LNP-mRNA cancer vaccines to intercept the disease progression from pre-invasive to invasive adenocarcinoma. Whole exome and RNA sequencing of a large cohort (>300) patients identified potential neoantigen candidates, with KRAS-G12C, KRAS-G12D and EGFR-L858R as the most frequently predicted shared neoantigens consistent with >40% GGO patient population harboring either mutant KRAS or EGFR driver oncogenes. LNP-mRNA vaccines targeting KRAS-G12C and EGFR-L858R showed marked immunogenicity as determined by ELISPOT assays. Moreover, KRAS-G12C vaccination induced CD4+ T cell responses whereas EGFR-L858R vaccination triggered CD8+ T cell responses. Both these vaccines are being tested in GGO immunoprevention studies. Our data suggest the potential of KRAS and EGFR vaccines in the treatment of early disease, particularly in EGFR mutant patients who fail to respond to immunotherapy. Citation Format: Yongfeng He, Sijin Luo Zhong, Bhavneet Bhinder, Geoffrey Markowitz, Arshdeep Singh, Eric Gardner, Myung Soo Ko, Nasser K. Altorki, Shaoyi Jiang, Vivek Mittal. LNP-mRNA neoantigen vaccines to intercept progression of pre-invasive to invasive lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4097.