The research on tumor vaccines has been moving forward in a difficult and tortuous way, although it has experienced many failures, but due to the discovery of tumor antigens and the in-depth research and understanding of the mechanisms of tumor-induced immune response and tumor evasion of immune surveillance, the research on tumor vaccines has made promising achievements in recent years. In 2006, the FDA approved Gardasil, the first oncology vaccine in human history, which can prevent human papillomavirus (HPV) type 16/18 infection for more than 5.5 years and effectively reduce the incidence of cervical cancer. In addition, another preventive vaccine for cervical cancer, Cervarix, and a therapeutic vaccine for prostate cancer, Provenge, were approved by FDA in 2009 and 2010 respectively. More new promising tumor vaccines are entering clinical trials. The personalized peptide vaccination (PPV) is one of them. PPV refers to the selection of up to four peptides matching the human leukocyte antigen A1 subtype (HLA-A1) from a series of candidate peptides according to the genetic structure and function of individual tumor patients to create a tumor vaccine, which can stimulate the specific immune response to the tumor and prolong the survival time of the patients. At present, a series of phase I, phase I/II and phase II clinical studies have been carried out, and this paper reviews the basic principles and clinical studies of individualized peptide vaccine. 1.The basic principle of PPV 1.1 Characteristics of candidate tumor antigen peptide of PPV Tumor antigen peptide is an important component of peptide vaccine, and tumor antigen must be degraded into short peptide and formed into peptide-MHC-TCR complex in the antigen presenting cell (APC) before it can be recognized by T cells and stimulate the corresponding cytotoxic T The peptide vaccine is designed to stimulate the cytotoxic T lymphocyte (CTL) response. The purpose of peptide vaccines is to deliver high doses of tumor antigen peptides to the major histocompatibility complex (MHC) molecules on the surface of APCs, therefore, suitable and effective tumor antigen peptides are important for the preparation of tumor vaccines. Tumor antigen peptides are restricted by MHC, only patients with identical MHC class I molecules can use the same peptide, and due to the heterogeneity of tumors, some tumor antigen peptides may induce immune tolerance rather than activate immune response. In contrast, PPV has the unique advantage of bypassing immune diversity and tumor heterogeneity over other tumor vaccines and can effectively avoid these problems. Ito M. et al. defined many tumor associated antigen (TAA) genes and related peptides that can be used as PPV vaccine antigens by cDNA expression cloning. For example, squamous cell carcinoma antigen recognized by T cells (SART) [6-9], p56lck [10], multidrug resistance associated protein 3 (MRP3) [11], and p56lck [12]. MRP3) [11], etc. K. Itoh et al [4] selected 31 MHC class I-restricted peptides possessing minimal optimal length for PPV preparation by studying peptide safety and immune potential, including SART2-93, SART2-161, SART3-109, SART3-302, SART3-309, SART3 -511, SART3-734, Lck-90, Lck-208, Lck-246, Lck-422, Lck-449, Lck-486, Lck-488, MPR3-503, MPR3-1293, CypB-129, MAP-432, WHSC2-103, WHSC2-141 HNRPL-140, HNRPL-501, UBE-43, UBE-85, PAP-213, PAP-248, PSA-248, EGFR-800, PSMA-624, EZH2-735, PTHrP-102. 12 types of HLA-A2, 14 types of HLA-A24, HLA-A26 There were 4 types of HLA-A2, 14 types of HLA-A24, 9 types of HLA-A26, and 9 types of HLA-A3. The 31 selected candidate peptides were provided by Peptide Laboratories I (San Diego, CA, USA) and American Peptide Corporation (Vista, CA, USA). Since vaccines prepared with greater than or equal to five peptides may produce intolerable skin adverse reactions such as pruritus and pain, no more than four peptides are currently used to prepare the vaccine 1.2 PPV Participant Selection Criteria Not all patients are suitable for clinical trials of PPV due to differences in individual immune function, and although there are no fixed criteria for patient enrollment in clinical trials of PPV, the The following draft criteria have been approved by the Kurume University Ethics Committee and registered in the UMIN Clinical Trials Registry (UMIN 2907). The details are as follows: (1) Patients with a definite diagnosis of malignancy; (2) A valid humoral immune response to at least 2 of the 31 candidate peptides; (3) Age between 20 and 80 years; (4) Eastern Cooperative Oncology Group (ECOG) behavioral score of 0 or 1; (5) Positive for HLA-A2 or HLA-A24 or HLA-A3 or HLA-A26; ( (6) expected survival time greater than or equal to 12 weeks; (7) no hepatitis B or C virus infection; (8) no significant abnormalities in hematological indicators, liver function, or kidney function. In addition, there are exclusion criteria: (1) patients with serious cardiopulmonary or other systemic disease; (2) acute infection; (3) history of severe allergy; (4) women who are pregnant or breastfeeding; (5) other conditions that have been assessed by the clinician as inappropriate for participation in the trial. All patients are required to have a complete understanding of the trial and to sign an informed consent form prior to participation. 1.3 Vaccine preparation The non-specific immune response induced by an inappropriate vaccine peptide is not only ineffective in tumor control, but may induce immune tolerance. Therefore, it is important to individually select the appropriate peptide from the 31 candidate peptides to prepare the vaccine for each patient. First, the peptide selected for PPV preparation should match the HLA type of the patient. Second, the immune function status of the patient before vaccination should be evaluated. komatsu N currently assesses the immune function of selected patients by the immunoglobulin G (Ig G) response present in the serum before vaccination by the multiplex bead-based LUMINEX assay with an average level of 10 FIU. This method can effectively predict the level of CTL response after vaccination and can reflect the safety, immunogenicity and possible clinical benefit of PPV. Thus, among the peptides matching the patient’s HLA type, up to the first four peptides that showed high IgG response were selected plus incomplete Förster adjuvant (Montanide ISA51; Seppic, Paris, France) to make a tumor vaccine. 1.4 Vaccination method PPV is administered by subcutaneous injection, and the vaccination schedule is usually weekly or biweekly subcutaneous injections. Clinical trials have shown that weekly vaccination induces a better immune response than biweekly, and the current recommended method is weekly for the first 6 weeks and biweekly thereafter, taking into account the efficacy and patient tolerance. In addition, PPV should be administered at different sites each time to prevent interactions between vaccine peptides. 2 .Progress in clinical studies of PPV In current clinical studies, PPV is mainly applied to patients with advanced tumors, including desmoresistant prostate cancer (CRPC), lung cancer, gastrointestinal tumors, bile duct cancer, pancreatic cancer, glioblastoma multiforme (GBM) and so on. A series of phase I, phase I/II, and phase II clinical studies have been conducted for different tumor types, and the current clinical studies are summarized below. 2.1 Desmoplastic resistant prostate cancer (CRPC) Phase I clinical trial of PPV in CRPC showed that some patients had enhanced cellular and humoral immune responses, while the level of prostate specific antigen (PSA) was decreased. In addition, a phase I/II trial was conducted in which 58 HLA-A2+ or HLA-A24+ CRPC patients were treated with PPV in combination with low-dose estramustine phosphate (EMP), showing a decrease in serum PSA levels in 76% of patients and a median survival of 17 months (95% CI, 12-25 months). This study demonstrated that PPV combined with low doses of cytotoxic agents could produce additional antitumor effects. Another phase II clinical study comparing the median survival time (MST) of PPV-treated (n=20) and historical controls (n=17) in patients with polyene paclitaxel (DOC)-resistant CRPC showed that the MST from the first day of vaccination to disease progression (progressive disease (PD) was 17.8 months in the PPV-treated group compared with 10.5 months in the historical control group. These preliminary findings suggest that PPV could be used as a new therapy for CRPC with disease progression after DOC treatment. Phase III randomized clinical trials of PPV application in DOC-resistant CRPC patients are currently underway. 2.2 Lung cancer A phase I/II clinical study of PPV in a small number of patients with refractory non-small cell lung cancer showed a median survival of 10.1-15.2 months, which was prolonged compared to patients without PPV. 10 patients with recurrent small cell lung cancer (SCLC) who were not responding to chemotherapy or radiotherapy participated in a phase II clinical trial of PPV. In a phase II clinical trial of PPV, the survival times were 25, 24.5 (alive), 10 (alive), 9.5, 6.5, and 6 months for the remaining six patients, except for four patients who discontinued treatment before the third vaccination due to disease progression. In another phase II clinical trial with 41 patients, the median survival time was 304 days, with a 1-year survival rate of 42% and no serious adverse events. 2.3 Gastrointestinal tumors In a phase I clinical trial of PPV in advanced colorectal cancer, 1 of 10 patients with HLA-24(+) showed partial responder (PR) and 1 had stable disease (SD) for more than 6 months. The Phase I trial of PPV in 13 patients with advanced gastric cancer showed prolonged survival and enhanced cellular and humoral immune responses after vaccination. In addition, a phase I/II clinical study of an oral 5-fluorouracil derivative (TS-1) in combination with PPV for advanced gastric or colorectal cancer showed that standard doses of TS-1 combined with PPV did not suppress the immune response in tumor patients, but rather maintained or enhanced the function of the body’s immune system. 2.4 Cholangiocarcinoma 25 patients participated in a phase II clinical trial of PPV in advanced cholangiocarcinoma, and both humoral and cellular immune responses against specific antigens were adequately induced after vaccination, with 80% of patients showing clinical benefit and prolonged OS after PPV vaccination. PPV is expected to be an effective treatment for patients with advanced cholangiocarcinoma. 2.5 Pancreatic cancer A phase I clinical trial of PPV application in 13 patients with HLA-A2+ or HLA-A24+ advanced pancreatic cancer has been conducted. The results showed clinical benefit in 85% of patients (11/13), as evidenced by tumor shrinkage or decreased tumor marker levels . Another phase II clinical study of PPV in combination with gemcitabine (GEM) showed that 21 patients were clinically effective and tolerated this regimen with an MST of 9 months and a 1-year survival rate of 38% and, for patients who showed a good immune response early on with PPV, an MST of 15 months, compared to GEM alone (MST of 5.7 months and 1-year survival rate of 18%). This treatment regimen significantly prolonged survival compared to GEM alone (MST of 5.7 months, 1-year survival rate of 18%) . 2.6 Glioblastoma multiforme (GBM) A phase I clinical trial of PPV for advanced GBM has been conducted in 21 patients who received greater than or equal to 6 PPV inoculations, of whom 5 developed PR, 8 presented with SD, and 8 with PD, with an MST of 20.7 months. In addition, the presence of effective levels of peptide-specific Ig G was detected in tumor lesions or cerebrospinal fluid of patients with good clinical response. 2.7 In addition, a series of phase I clinical trials in patients with metastatic renal cell carcinoma, malignant melanoma, bladder cancer, and gynecologic tumors have demonstrated that PPV induces a strong and potent immune response and is safe and well tolerated. 3. Conclusion In recent years, the research of tumor vaccine has gained more and more attention, and individualized therapy is also a new idea of tumor treatment. PPV organically combines tumor vaccine and individualized therapy, which indicates a new direction for the development of tumor vaccine. Although it is still in the research stage, a series of phase I, phase I/II, and phase II clinical studies have demonstrated that PPV can prolong patients’ OS and improve their survival status, and it is safe and reliable, which undoubtedly brings new hope for patients with advanced tumors for whom other therapies are ineffective. However, there are some outstanding problems in the current PPV studies, one is the lack of multicenter clinical trials with large samples, and the other is that there are no reliable indicators that can predict the efficacy of patients after PPV vaccination. In the future, we expect that more rationally designed multicenter phase III clinical studies with large samples can be conducted as soon as possible.