An EGFR L858R mutation identified in 1862 Chinese NSCLC patients can be a promising neoantigen vaccine therapeutic strategy

Abstract

BackgroundThis study aimed to develop a vaccine that targets mutation-derived neoantigen in Chinese non-small-cell lung cancer (NSCLC).MethodsA cohort of 1862 Chinese NSCLC patients who underwent targeted sequencing with a 1021-gene panel was investigated. HLA typing was done using OptiType v1.0 and neoantigens were predicted by netMHCpan v4.0. HLA LOH was inferred using the lohhla algorithm and TMB were quantified by counting the total number of non-synonymous ones based on our panel data. CIBERSORT was utilized to estimate the TME in different EGFR mutant subtype by using TCGA data.ResultsHLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th. EGFR L858R (22.61%) was the most prevalent gene variant. The binding affinity (IC50 MT = 22.9 nM) and shared frequency (2.93%) of EGFR L858R in combination with HLA-A*33:03 were optimal. In a subsequent further analysis on immunological features of EGFR mutant subtypes, 63.1% HLA loss of heterozygosity LOH (HLA LOH) and 0.37% (7 of 1862) B2M aberrations were found in our population, both had no significant association with EGFR mutant subtypes suggesting that the process of antigen presentation involved HLA LOH and B2M mechanisms in EGFR L858R is working. Tumor mutation burden (TMB) was investigated by utilizing our panel and showed that EGFR L858R had the lowest TMB compared with other EGFR mutant subtypes. In addition, analysis of 22 immune cell types from The Cancer Genome Atlas (TCGA) data showed EGFR L858R was correlated with low level of CD8 T cells, activated CD4 memory T cells and elevated level of macrophage M2 suggesting an inhibited tumor microenvironment (TME).ConclusionOur study identified that EGFR L858R neoantigen had the potential to generate cancer vaccines in NSCLC patients with HLA A*33:03. The neoantigen-based vaccines may become an effective salvage regimen for EGFR L858R subgroup after targeted therapy or immune checkpoint inhibitors (ICIs) failure.

Multicellular ecotypes shape progression of lung adenocarcinoma from ground-glass opacity toward advanced stages

“…These two patients also showed an HLA-A11.01 allele type, which is seemingly a dominant HLA allele type (>40%) in Asian individuals. 48 The distributions of HLA-A11.01 were also overrepresented in non-progressors as shown by another study ( Figures S7 E and S7F). Given the limited availability of clinical samples collected at stages featuring GGO radiological patterns, we were unable to carry out paired analyses of both WES and HLA peptidome in the same sample.…”

Epidermal Growth Factor Receptor-Targeted Neoantigen Peptide Vaccination for the Treatment of Non-Small Cell Lung Cancer and Glioblastoma

“…HLA-A*31:01, A*33:01, B*08:01, and B*27:05 were identified to strongly bind L858R-derived neoantigens but not the corresponding wild-type peptides, whereas HLA-A*11:01 and A*03:01 bound to peptides encompassing the E746_A750del neoantigens with high affinity. These results were supported by the work of a Chinese team that investigated a large cohort of 1862 Chinese NSCLC patients for neoepitopes [ 40 ]. Among this cohort, EGFR mutations occurred at a very high frequency, with L858R and E746_A750del being the most dominant, with frequencies of 23% and 13% respectively.…”

“…For example, data mining of the TCGA showed that one-third of patients with early-stage lung adenocarcinoma bear either EGFR L858R or E746_A750del and at least one HLA allele binding neoantigens encompassing these 2 mutations. Within the cohort of Chinese NSCLC patients, L858R and HLA-A*33:03 coexist in 2.93% of patients while E746_A750del and HLA-A*11:01 cooccurred in 5.6% of the NSCLC patients [ 40 ]. The coexistence of these EGFR mutations and HLA alleles presenting them in patients may bring some immune protection as these patients exhibited better disease-free (DFS) and overall survival (OS) than other patients, as shown by the analysis of the TCGA data.…”

The Efficacy of Tumor Mutation Burden as a Biomarker of Response to Immune Checkpoint Inhibitors

“…Because neoantigens are personalized, these tumor vaccines are effective in inducing tumor-specific T cells without targeting normal cells. Hundreds of synthetic long peptides, RNA-, DNA-, and dendritic cell-based vaccines have reached clinical validation trials, and one successful example is a neoantigen peptide vaccine for EGFR-mutated non-small cell lung cancer [ 88 ]. As the field of cancer treatment evolves, the clinical methodologies utilized to induce tumor regression and subsequently create lasting anti-tumor immune memory will continue to advance.…”