Nobukazu Komatsu

Kurume University · Department of Immunology

Background Many clinical trials of immune checkpoint blockade-based combination therapies are under way. Vaccine therapy is a promising partner of combination therapies. We have developed a personalized peptide vaccination and conducted clinical trials of it in patients with various cancers. At the present time, we have only a limited number of bio...

Endometrial cancer is the most prevalent gynecological cancer in developed countries. Although the prognosis of endometrial cancer is better than that of other gynecological cancers, the prognosis of advanced endometrial cancer is still poor and thus new therapeutic modalities, such as immune therapies, are urgently required. For the further develo...

Cancer immunotherapy including vaccine therapy is a promising modality for cancer treatment, but few patients show its clinical benefits currently. The identification of biomarkers that can identify patients who will benefit from cancer immunotherapy is thus important. Here, we investigated the potential utility of the circulating cell-free DNA (cf...

Peptide‑based cancer vaccines have failed to provide sufficient clinical benefits in order to be approved in clinical trials since the 1990s. To understand the mechanisms underlying this failure, the present study investigated biomarkers associated with the lower overall survival (OS) among 2,588 patients receiving personalized peptide vaccination...

Background: We conducted a phase III trial of personalized peptide vaccination (PPV) for human leucocyte antigen (HLA)-A24+ recurrent glioblastoma to develop a new treatment modality. Methods: We randomly assigned 88 recurrent glioblastoma patients to receive PPV (n=58) or the placebo (n=30) at a 2-to-1 ratio. Four of 12 warehouse peptides selec...

Currently prophylactic HPV16/18 L1 virus-like particle (VLP) vaccines are employed with great success for the prevention of HPV infection. However, limited information is available regarding the immune responses against human papillomavirus (HPV) 16/18 L1 subsequent to HPV16/18 L1 VLP vaccination, primarily due to the lack of widely used assays for...

Table S1. HLA restriction of 10 peptides of KRM‐10.

A phase I study of a new cancer vaccine (KRM-10), consisting of a mixture of 10 different short peptides, was conducted for patients with advanced gastrointestinal cancers. Primary or secondary endpoints included the dose-limiting toxicity (DLT), or safety and immune responses, respectively. Peptide-specific cytotoxic T lymphocytes (CTL) and immuno...

Personalized peptide vaccination (PPV) is an attractive approach to cancer immunotherapy with strong immune-boosting effects conferring significant clinical benefit. However, as with most therapeutic agents, there is a difference in clinical efficacy among patients receiving PPV. Therefore, a useful biomarker is urgently needed for prognosticating...

Purpose: The prognosis of platinum-based chemotherapy-resistant metastatic urothelial cancer of the bladder remains poor. Personalized selection of the right peptides for each patient could be a novel approach for a cancer vaccine to boost anticancer immunity. Experimental design: In this randomized, open-label, phase II study, patients ages ≥18...

Objective . To evaluate safety and immune responses of personalized peptide vaccination (PPV) for hepatitis C virus- (HCV-) positive advanced hepatocellular carcinoma (HCC). Patients and Methods . Patients diagnosed with HCV-positive advanced HCC were eligible for this study. A maximum of four HLA-matched peptides were selected based on the preexis...

The heterogeneity expression of tumor-associated antigens (TAA) and variability of human T cell repertoire suggest that effective cancer vaccine requires induction of a wide breadth of cytotoxic T lymphocyte (CTL) specificities. This can be achieved with vaccines targeting multiple TAA. We evaluated the safety and immune dynamics of a cancer vaccin...

Since the prognosis of advanced colorectal cancer (aCRC) remains poor, development of new therapeutic approaches, including immunotherapy, would be highly desirable. In the current study, we conducted a phase II study of personalized peptide vaccination (PPV) in 60 previously treated aCRC patients, who had failed at least one regimen of standard ch...

The prognosis of non-small cell lung cancer (NSCLC) patients who failed two or more treatment regimens remains very poor. We conducted a phase II study to explore the feasibility of personalized peptide vaccination (PPV), in which peptides are selected and administered based on the pre-existing host immunity before vaccination, as a third or more l...

PD-1 expression in peripheral blood T-cells has been reported in several kinds of cancers, including lung cancer. However, the relationship between PD-1 expression in peripheral blood T-cells and prognosis after treatment with a cancer vaccine has not been reported. To elucidate this relationship, we analyzed PD-1 expression in the peripheral blood...

Haptoglobin (HP) is an acute-phase protein induced by inflammatory stimuli. Its serum level varies in several clinical conditions and among individuals. The common HP alleles (HP(1) and HP(2)), HP complete deletion allele (HP(del)), and two SNPs (rs5472 and rs2000999) have been reported to be possible genetic determinants of serum HP levels so far....

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with clinical response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, in patients with non-small cell lung cancer (NSCLC). However, humoral immune responses to EGFR in NSCLC patients have not been well studied. In this study, we investigated the clin...

Although a peptide vaccination is potentially useful for cancers, there are some patients who do not show clinically beneficial response to this treatment. Previously, we have demonstrated gene expression profiling of pre-vaccination peripheral blood mononuclear cells in advanced castration-resistant prostate cancer patients with personalized pepti...

Along with recent advancements in the field of basic and clinical immunology over the past several decades, cancer immunotherapy has shown progress as a novel treatment modality against cancer. We have developed a novel immunotherapeutic approach, the personalized peptide vaccination (PPV), in which, 2-4 suitable peptides are selected based on the...

Pancreatic cancer is one of the most aggressive cancers with a median survival time (MST) of <6 months in chemotherapy-resistant patients. Therefore, the development of novel treatment modalities is needed. In the present study, a phase II study of personalized peptide vaccination (PPV) was conducted, in which vaccine antigens were selected and adm...

Juzentaihoto (JTT) is a well-known Japanese herbal medicine, which has been reported to modulate immune responses and enhance antitumor immunity in animal models. However, it is not clear whether JTT has similar effects on humans. In particular, there is little information on the effects of JTT in antigen-specific immunity in cancer patients. Here...

Supplementary Table 1. The list of peptide candidates employed for personalized peptide vaccination. Supplementary Table 2. Humoral and cellular immune responses to the vaccine antigens before and after vaccination in each patient of the PPV plus JTT group. The humoral immune responses specific to the vaccine peptides were determined by peptide-spe...

Haptoglobin (Hp) is a well-known acute-phase protein that possibly has influence on tumors through the immune response. This study was conducted to evaluate the correlation between Hp expression and the effect of treatment by cancer peptide vaccines in advanced castration-resistant prostate cancer (CRPC) patients. Hp expression was measured by RT-P...

Persistent infection of human papillomavirus (HPV) types 16 and 18 causes cervical cancer. To better understand immune responses to the prophylactic vaccine, HPV 16/18 L1 virus-like particles (HPV-VLPs), we investigated B cell epitopes of HPV16 L1-derived peptides. Sera from mice immunized with HPV-16/18 L1 VLPs were analyzed for their IgG titers a...

Because only a subset of patients show clinical responses to peptide-based cancer vaccination, it is critical to identify biomarkers for selecting patients who would most likely benefit from this treatment. The authors characterized the gene expression profiles in peripheral blood of vaccinated patients to identify biomarkers to predict patient pro...

Background: Since the prognosis of advanced pancreatic cancer remains poor, development of novel therapeutic approaches, including cancer vaccine, would be highly desirable. We conducted a phase II study of personalized peptide vaccine (PPV) in chemotherapy-resistant advanced pancreatic cancer patients. Methods: Forty-one advanced pancreatic cancer...

Considering that the prognosis of patients with advanced biliary tract cancer (BTC) remains very poor, with a median survival of less than 1 year, new therapeutic approaches need to be developed. In the present study, a phase II clinical trial of personalized peptide vaccination (PPV) was conducted in advanced BTC patients to evaluate the feasibili...

Since the prognosis of small cell lung cancer (SCLC) remains poor, development of new therapeutic approaches, including immunotherapies, would be desirable. In the current study, to evaluate immunological responses in refractory SCLC patients, we conducted a small scale phase II clinical trial of personalized peptide vaccination (PPV), in which vac...

(Introduction) Recently, cancer vaccines have emerged as one of the promising therapeutic options. However, it is still difficult to predict clinical responses in vaccinated patients prior to vaccination. For further development of this field, it would be of critical importance to identify biomarkers for selecting patients adequate for cancer vacci...

The majority of peptide-based cancer vaccines under development are for human leukocyte antigen (HLA)-A2- or -A24-positive patients. To overcome this limitation, we conducted a phase I clinical study of peptide vaccines designed for cancer patients with six different HLA-A types. Eligible patients were required to have failed prior standard cancer...

The purpose of this study was to investigate severe adverse events (SAEs) after therapeutic peptide vaccination for advanced cancer patients. We investigated SAEs following personalized peptide vaccinations in 500 advanced cancer patients, including 174 prostate, 74 colon, 51 pancreatic and 43 gastric cancer patients. The number of vaccination cycl...

To investigate immunological biomarkers to predict overall survival of advanced cancer patients under treatment with personalized peptide vaccination, correlations between overall survival and biomarkers, including cytotoxic T lymphocyte (CTL) and immunoglobulin G (IgG) responses to the vaccinated peptides, were investigated in 500 advanced cancer...

• To investigate the safety and immune responses of 12 consecutive weeks of once-weekly personalized peptide vaccine (PPV) administration in patients with advanced urothelial carcinoma (UC) for whom therapy with methotrexate, vinblastine, adriamycin and cisplatin (MVAC) has failed. • A phase I trial was designed. Ten patients with MVAC-refractory a...

Vaccine therapies are increasingly being used for the treatment of various diseases, and the antigen molecules themselves are being expanded from whole microorganisms to fine molecules such as peptides. Accordingly, there is a need for new adjuvants to support these new applications. In this paper, we used pharmaceutical grade mineral oil and sorbi...

To facilitate the development of a peptide-based cancer vaccine for prostate cancer patients, we examined whether any of the 13 peptides previously reported to induce HLA-class I-restricted cytotoxic T lymphocyte (CTL) activity in HLA-A3 supertype (-A3, -A11, -A31 and -A33)-positive prostate cancer patients are also capable of inducing CTLs restric...

We evaluated the safety of, and clinical and immune responses to personalized peptide vaccination with gemcitabine (GEM) as the first line therapy in patients with non-resectable pancreatic cancer. Pre-vaccination peripheral blood mononuclear cells (PBMCs) and plasma were prepared to examine cellular and humoral responses to 14 and 16 peptides in h...

Most of the recent randomised clinical trials of therapeutic cancer vaccines have failed to demonstrate a meaningful therapeutic benefit to patients over existing treatments. Furthermore, some clinical trials have demonstrated a detrimental effect on patients, resulting in poorer outcomes. These unexpected results have shed light on several importa...

(Cancer Sci 2010; 101: 601–608) We previously reported that personalized peptide vaccine (PPV) therapy in combination with leutenizing hormone-releasing hormone (LH-RH) analog and estramustine phosphate in certain cases is safe and capable of inducing both immune responses and clinical responses for metastatic castration-resistant prostate cancer (...

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 canc...

To better understand the unbalanced immunoglobulin production that occurs in pollinosis, we measured the levels of IgG, IgA, and IgE reactive to either Japanese cedar pollen, Cry j 1 protein, or Cry j 2 protein in the sera of pollinosis patients. As expected, the levels of these immunoglobulins (Igs) reactive to the three antigens were significantl...

One-fifth of the Japanese population is positive for HLA-A26, but few peptides are available as potential cancer vaccines for HLA-A26-positive cancer patients. The objective of this study was to identify peptide vaccine candidates for HLA-A26-positive cancer patients. The HLA-A*2601-crossbinding activity of 24 peptides currently under clinical tria...

C35-44 peptide is a well known HLA-A2-restricted CTL epitope originating from hepatitis C virus (HCV) core protein. It was reported that the majority of HCV positive patients had significant levels of serum IgG specific to this peptide. This study addressed whether C35-44 peptide could induce CTL activity restricted to various HLA class IA alleles...

Hepatitis C virus (HCV) infection has a high risk of liver cirrhosis and hepatocellular carcinoma at later stages. We recently identified a peptide derived from the HCV core protein capable of inducing both cellular and humoral responses to nearly all HCV-positive patients in Japan with different human leukocyte antigen (HLA)-class I-A alleles. To...

To investigate the safety and immunological responses of personalized peptide vaccination in combination with oral administration of UFT and UZEL for metastatic colorectal carcinoma (mCRC), fourteen patients were enrolled in the present study. Peptides were determined based on the presence of peptide-specific cytotoxic T lymphocyte precursors and I...

We previously reported peptide vaccine candidates for HLA-A3 supertype (-A3, -A11, -A31, -A33)-positive cancer patients. In the present study, we examined whether those peptides can also induce cytotoxic T lymphocyte (CTL) activity restricted to HLA-A2, HLA-A24, and HLA-A26 alleles. Fourteen peptides were screened for their binding activity to HLA-...

We previously reported the SART3 gene to be a tumor-rejection antigen gene encoding a peptide at positions 109-118 (SART3(109-118)) with the ability to induce HLA-A24-restricted cytotoxic T lymphocytes. In this study, we investigated both humoral and cellular responses to this peptide in cancer patients with alleles other than HLA-A24 to explore th...

To evaluate the immunological responses of personalized peptide vaccination combined with low-dose glucocorticoids for advanced hormone refractory prostate cancer (HRPC) patients (pts). Eleven pts with advanced HRPC were treated with the vaccination and low-dose glucocorticoids; 6 pts with 10 mg/day of prednisolone (PDL) followed by 1 mg/day of dex...

The determination of immunogenic peptides of hepatitis C virus (HCV) is pivotal for vaccine development. We previously reported that the majority of patients infected with HCV have significant levels of IgG specific to an HCV-derived peptide at positions 35-44 of core protein (C35-44), a major epitope recognized by cellular immunity. This study add...

When expressed in mammalian cells, the nucleocapsid (N) and membrane (M) proteins of the severe acute respiratory syndrome coronavirus (SARS-CoV) are sufficient to form pseudoparticles. To identify region(s) of the N molecule required for pseudoparticle formation, we performed biochemical analysis of the interaction of N mutants and M in HEK293 cel...

The polycomb group protein enhancer of zeste homolog 2 (EZH2) is linked to aggressive prostate cancer and could be an appropriate target in specific immunotherapy. In this study, we attempted to identify EZH2-derived peptides that have the potential to generate cancer-reactive cytotoxic T lymphocytes (CTLs) in human leukocyte antigen (HLA)-A2+ pros...

To assess the safety and immune responses to a personalized peptide vaccination of hepatitis C virus (HCV) 1b-derived peptides, 12 HCV1b-positive patients, who were unresponsive to interferon-based therapy, were enrolled in this study. The reactivity of the pre-vaccination peripheral blood T cells and plasma IgG to four vaccine candidate peptides c...

Hepatitis C virus (HCV) frequently causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma after long-term persistent infection. Among various genotypes of HCV, HCV1b is resistant to standard interferon therapy, and thus the development of new treatment modality is needed. To provide a scientific basis for specific immunotherapy for HCV1b...

One of the longstanding challenges in the treatment of pancreatic cancer, the fifth most common cancer worldwide, is to establish a simple and reliable diagnostic marker for the disease. This study examined whether or not the plasma levels of IgG antibodies (IgGs) reactive to peptides derived from the prostate stem cell antigen (PSCA), which is hig...

Squamous cell carcinoma antigen (SCCA) is a useful marker for SCCs. In this study, we attempted to identify SCCA-derived peptides that could be applied in the development of specific immunotherapy for HLA-A24+ cancer patients with SCC or non-SCC. A variety of SCC and non-SCC lines were examined for their expression of SCCA mRNA using quantitative P...

Since virus-specific cytotoxic T lymphocytes (CTLs) play a critical role in preventing the spread of hepatitis C virus (HCV), vaccine-based HCV-specific CTL induction could be a promising strategy to treat HCV-infected patients. In this study, we tried to identify HCV2a-derived epitopes, which can induce human leukocyte antigen (HLA)-A24-restricted...

One of the longstanding challenges in the treatment of pancreatic cancer, the fifth most common cancer worldwide, is to establish a simple and reliable diagnostic marker for the disease. This study examined whether or not the simultaneous measurement of plasma levels of IgG antibodies (IgGs) reactive to peptides recognized by cytotoxic T lymphocyte...

In 103 patients without occult neoplastic cells (ONCs) in the lymph node sinuses, the 5-year relapse-free survival (RFS) rate and overall survival (OS) rate were 90.2% and 91.8%, respectively. In 21 patients with ONCs, the 5-year RFS and OS rates were 34.9% and 62.3%, respectively. There were marked differences of survival between the two groups (p...

In 72 patients without occult neoplastic cells (ONCs) in their lymph node sinuses, the 5-year relapse-free survival (RFS) rate and overall survival (OS) rate were 71.3% and 69.2%, respectively. In 33 patients with ONCs, the 5-year RFS rate and OS rate were 33.9% and 31.3%, respectively. There was a marked difference of survival between the two grou...

The primary goal of this phase I study was to assess the safety and immunologic responses of personalized peptide vaccination for patients with advanced malignant glioma. Twenty-five patients with advanced malignant glioma (8 grade 3 and 17 grade 4 gliomas) were evaluated in a phase I clinical study of a personalized peptide vaccination. For person...

Despite scientific advances, the therapeutic options for hepatitis C virus (HCV) are limited by poor response rates. HCV1b is particularly resistant to standard interferon therapy. The inhibition of the progression of chronic hepatitis and liver cirrhosis and the prevention of the occurrence and recurrence of hepatocellular carcinoma (HCC) are impo...

Colon cancer is one of the major malignant tumours for which the development of a new treatment modality is needed. To provide the scientific basis for a specific immunotherapy for colon cancer, we looked for tumour-associated antigens recognised by cytotoxic T lymphocytes (CTLs) from human leukocyte antigen (HLA)-A2+ colon cancer patients. We repo...

To provide a scientific basis for specific immunotherapy of colon cancer, this study focused on the identification of tumor-associated antigens recognized by HLA-A2-restricted and cancer-reactive cytotoxic T lymphocytes (CTLs) from tumor-infiltrating lymphocytes (TIL) of a colon cancer patient. We identified a gene coding a member of the ATP-bindin...

This study was designed to compare the prediction of recurrence based on detection of occult neoplastic cells (ONCs) in lymph nodes or using specific criteria to identify patients at high risk of recurrence/metastasis among 105 patients with Dukes' C colorectal cancer. Prediction of recurrence based on the detection of ONCs had a sensitivity of 50....

This study compared the prediction of recurrence based on detection of occult neoplastic cells (ONCs) in lymph nodes or using 3 criteria to identify high-risk patients among 72 patients who had Dukes' A colorectal cancer with or without proper muscle invasion. Predicting recurrence based on the detection of ONCs had a sensitivity of 40.0% (2/5) and...

In order to determine highly immunogenic severe acute respiratory syndrome coronavirus (SARS-CoV) epitope peptides capable of inducing long-lasting immunity, we first screened immunoglobulin-G (IgG) antibodies reactive to 197 different overlapping 15-mers from the SARS-CoV proteins in the sera of three infected patients. Forty-two peptides among th...

The purpose of this work was to provide a scientific basis for specific immunotherapy of colon cancer. This study focused on identification of colon tumor-associated antigens and HLA-A2-restricted and tumor-reactive cytotoxic T lymphocytes (CTLs) generated from tumor-infiltrating lymphocytes of a colon cancer patient. A gene expression cloning meth...

The epidermal growth factor receptor (EGFR) is one of the most appropriate target molecules for cancer therapy because of its high expression in epithelial cancers. A novel EGFR-tyrosine-kinase inhibitor, ZD1839, has been approved as a drug for non-small cell lung cancer (NSCLC), and many other agents are now being tested in clinical trials. Cytoto...

Protein-bound polysaccharide K (PSK), which is derived from mushrooms belonging to the Basidiomycetes genus, has been clinically used as a biological response modifier (BRM) for the treatment of epithelial cancer patients in Japan and other Asian countries. There are a large number of studies on the biological activities of PSK as regards the activ...

SART3 has been identified as a tumor antigen recognized by cytotoxic T-lymphocytes. Subcellular localization of SART3 is still controversial, although it has been studied extensively. In this study, we established an anti-SART3 monoclonal antibody (mAb) to analyze the subcellular localization of SART3 in tumor specimens. Immunohistochemical analysi...

Shiga toxin (Stx) has an A1-B5 subunit structure, and the A subunit is an RNA N-glycosidase that inhibits cellular protein synthesis. We previously reported that in Caco-2 cells Stx induced cytokines and that the RNA N-glycosidase activity was essential for the cytokine induction. It is known that the binding of the Stx-B subunit to its receptor gl...