The field of cancer immunotherapy has moved forward drastically in the past 20 years, since many tumor-associated antigens (TAA) have been identified. Although various approaches for therapeutic cancer immunotherapies, including peptide-based vaccines, have been developed and clinically examined, the complexity and diversity of tumor cell characteristics and host immune cell repertoires seem to limit the therapeutic efficacy of this treatment modality. Considering the diversity of immune responses against heterogeneous tumor cells, tailored selections of vaccine antigens appropriate for individual patients could be a rational approach for developing effective cancer vaccines. We have developed a novel immunotherapeutic approach called personalized peptide vaccine (PPV), in which a maximum of four human leukocyte antigen (HLA)-matched vaccine peptides were selected based on the pre-existing host immunity before vaccination. We conducted a series of phase I and phase II clinical trials of PPV, which have shown better antigen-specific immune responses and promising clinical outcomes in patients with various types of advanced cancers. Further randomized phase III trials would be recommended to prove the clinical benefits of PPV. In addition, novel biomarkers for selecting patients who would benefit most from PPV remain to be identified.

Our report should make it easier to diagnose transition zone cancer. The 72% biochemical PSA cure rate is significantly higher than the 49% cure rate for peripheral zone cancer. Since cancer volume and percent Gleason grade 4/5 disease were the same in these 2 groups matched by cancer volume, the differences in behavior of peripheral and transition zone cancers must be sought at the molecular level unless anatomical location alone explains the differences in progression. Pathologists should differentiate transition from peripheral zone cancer when analyzing radical prostatectomy specimens.

Personalized peptide vaccination (PPV) combined with chemotherapy could be a novel approach for many cancer patients. In this randomized study, we evaluated the anti-tumor effect and safety of PPV plus low-dose estramustine phosphate (EMP) as compared to standard-dose EMP for HLA-A2- or -A24-positive patients with castration resistant prostate cancer. Patients were randomized into groups receiving either PPV plus low-dose EMP (280 mg/day) or standard-dose EMP (560 mg/day). After disease progression, patients were switched to the opposite regime. The primary end point was progression-free survival (PFS). We randomly assigned 28 patients to receive PPV plus low-dose EMP and 29 patients to receive standard-dose EMP. Nineteen events in the PPV group and 20 events in the EMP group occurred during the first treatment. Median PFS for the first treatment was 8.5 months in the PPV group and 2.8 months in the EMP group with a hazard ratio (HR) of 0.28 (95% CI, 0.14-0.61; log-rank P = 0.0012), while there was no difference for median PFS for the second treatment. The HR for overall survival was 0.3 (95% CI, 0.1-0.91) in favor of the PPV plus low-dose EMP group (log-rank, P = 0.0328). The PPV plus low-dose EMP was well tolerated without major adverse effects and with increased levels of IgG and cytotoxic-T cell responses to the vaccinated peptides. PPV plus low-dose EMP was associated with an improvement in PSA-based PFS as compared to the standard-dose EMP alone.

Since both tumor cells and host immune cell repertoires are diverse and heterogeneous, immune responses against tumor-associated antigens should differ substantially among individual cancer patients. Selection of suitable peptide vaccines for individual patients based on the preexisting host immunity before vaccination could induce potent anti-tumor responses that provide clinical benefit to cancer patients. We have developed a novel immunotherapeutic approach of personalized peptide vaccination (PPV) in which a maximum of four human leukocyte antigen (HLA) class IA-matched peptides are selected for vaccination among pooled peptides on the basis of both HLA class IA type and the preexisting host immunity before vaccination. In this review, we discuss our recent results of preclinical and clinical studies of PPV for various types of advanced cancer.

Increase in cellular and humoral immune responses, and decrease in PSA level in some patients support further development of peptide-based immunotherapy for hormone refractory prostate cancer.