Background: Oncoantigens are oncogenic and high immunogenicity proteins specifically expressed in cancers, and are promising targets for personalized immunotherapy. Methods: We have established a strategy to identify new oncoantigens; i) screening of genes expressed in the majority of 120 lung cancers with cDNA microarray covering 27,648 genes, ii) verification of no expression of these genes in normal tissues, iii) validation of the clinicopathological significance of their expression with tissue microarray covering 400 lung cancers, iv) characterization of their role in the growth or invasiveness of cancer cells by RNAi and cell growth/invasion assays, v) screening of the epitope peptides recognized by HLA-A*0201- or A*2402-restricted cytotoxic T lymphocyte (CTL) for clinical trials. Results: We identified dozens of 10-amino-acid peptides from 45 oncoantigens, each of which was a candidate to be presented on the surface of HLA-A*0201 or HLA-A*2402 that induced CTL response. We conducted a phase I study for HLA-A*2402-positive, advanced non-small cell lung cancer patients who failed to standard therapy, using the combination of three peptides from LY6K, CDCA1, and KIF20A mixed with adjuvant once a week. 20 evaluable patients have been enrolled, and this cancer vaccine therapy demonstrated tolerability and had very high immunogenicity to induce antigen-specific CTLs in cancer patients. Disease control rate including one complete response was 50%. The patients showing LY6K-specific CTL responses demonstrated a longer overall survival than those without CTL induction. The patients with CTL induction for multiple peptides were likely to show better clinical outcomes. We are also screening predictive and monitoring biomarkers for peptide vaccine therapy through immunogenomics approach by analyzing pattern of CTL response, genomic/proteomic profiles of CTLs, cancer tissues and serum, as well as genetic variation of patients and identified various candidate biomarkers detectable in cancer tissues and/or serum. Conclusions: Current data of the cancer vaccine therapy coupled with screening of companion diagnostics warrants further clinical studies to develop more personalized and effective immunotherapy. Clinical trial information: NCT01069575