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Kyogo Itoh - One of the best experts on this subject based on the ideXlab platform.

  • phase i clinical study of a personalized peptide vaccination available for six different human leukocyte antigen hla a2 a3 a11 a24 a31 and a33 positive patients with advanced cancer
    Experimental and Therapeutic Medicine, 2011
    Co-Authors: Akira Yamada, Masanori Noguchi, Nobukazu Komatsu, Shigetaka Suekane, Shigeru Yutani, Fukuko Moriya, Takashi Mine, Kosuke Momozono, Koichiro Kawano, Kyogo Itoh
    Abstract:

    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 therapies and to be positive for the HLA-A2, -A24 or -A3 (A3, A11, A31 and A33) supertype. Three sets of 8 candidate peptides (24 peptides in total) were provided for vaccination to HLA-A2(+), HLA-A24(+) and HLA-A3(+) patients, respectively. Personalization of the vaccination peptides from the candidate pool was made by considering the patients' HLA types and pre-existing levels of IgGs to the candidate peptides. Seventeen patients were enrolled in this study. The peptide vaccinations were well tolerated in all patients with no vaccine-related severe adverse events. Augmentation of cytotoxic T lymphocyte (CTL) or IgG responses specific to the vaccinated peptides was observed in 11 or 10 out of 13 cases tested, respectively. This new type of vaccine is recommended for phase II clinical trial because of its tolerability and the immune responses to the vaccinated peptides.

  • kinesin superfamily protein derived peptides with the ability to induce glioma reactive cytotoxic t lymphocytes in human leukocyte antigen a24 glioma patients
    Oncology Reports, 2007
    Co-Authors: Mamoru Harada, Kyogo Itoh, Yuki Ishihara, Ryuya Yamanaka
    Abstract:

    One promising modality in the treatment of malignant glioma is specific immunotherapy. However, this modality requires information about target antigens and their epitope peptides that are recognized by T cells. In this study, we searched for new target candidates in specific immunotherapy for malignant glioma by utilizing cDNA microarray technology to compare gene expressions in malignant glioma tissues to those in benign glioma and a panel of normal tissues. The selected genes included three members of the kinesin superfamily proteins (KIFs): KIF1C, KIF3C, and KIF21B. RT-PCR showed that these three genes were expressed in the majority of glioma cell lines. These antigen-derived 25 peptides, which had the ability to bind to human leukocyte antigen (HLA)-A24 molecules, were first screened for their ability to be recognized by the immunoglobulin G of glioma patients, and then tested for their potential to induce peptide-specific and glioma-reactive cytotoxic T lymphocytes (CTLs) from the peripheral blood mononuclear cells of HLA-A24 + glioma patients. The results showed that the KIF1C 149-198 and KIF3C 512-520 peptides efficiently induced HLA-A24-restricted and glioma-reactive CD8 + T cells. These results suggest the existence of KIF-reactive CTL precursors in glioma patients, and should facilitate the development of specific immunotherapies for malignant glioma.

  • prostatic acid phosphatase as a target molecule in specific immunotherapy for patients with nonprostate adenocarcinoma
    Journal of Immunotherapy, 2005
    Co-Authors: Yi Wang, Mamoru Harada, Hirohisa Yano, Sachiko Ogasawara, Hiroko Takedatsu, Yoshimi Arima, Satoko Matsueda, Akira Yamada, Kyogo Itoh
    Abstract:

    Prostatic acid phosphatase (PAP) is one of the prostate-related antigens that are applicable to specific immunotherapy for patients with prostate cancer. In this study, we determined whether or not PAP could be a target molecule in specific immunotherapy for patients with nonprostate cancer. Avariety of adenocarcinoma cell lines were examined for their PAP expression at the mRNA and protein levels by reverse transcription polymerase chain reaction and western blot analysis, respectively. Considerable percentages of colon, gastric, and breast cancer cell lines were found to be positive for PAP at both the mRNA and the protein levels. The PAP expression in cancer tissues was also confirmed by immunohistochemical staining. In addition, we examined whether cancer-reactive cytotoxic T lymphocytes (CTLs) could be induced from peripheral blood mononuclear cells (PBMCs) of human leukocyte antigen (HLA) A24 + nonprostate cancer patients by in vitro stimulation with a PAP peptide. As a result, tumor-specific CTLs could be induced from the PBMCs of HLA-A24 + colon and gastric cancer patients. Their cytotoxicity against HLA-A24 + cancer cells was dependent on PAP peptide-specific and CD8 + T cells. These findings indicate that PAP could be a target molecule in specific immunotherapy for patients with nonprostate adenocarcinomas including colon and gastric cancers.

  • a prostate stem cell antigen derived peptide immunogenic in hla a24 prostate cancer patients
    The Prostate, 2004
    Co-Authors: Satoko Matsueda, Kyogo Itoh, Yuki Ishihara, Masanori Noguchi, Akihisa Yao, Rika Ogata, Mamoru Harada
    Abstract:

    BACKGROUND We attempted to identify prostate stem cell antigen (PSCA)-derived peptides immunogenic in HLA-A24+ prostate cancer patients. METHODS Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with each of three different PSCA-derived peptides, which were prepared based on the HLA-A24 binding motif, and their peptide-specific and HLA-A24-restricted anti-tumor responses were examined. Plasma levels of immunoglobulin G (IgG) against PSCA peptides were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Among three PSCA peptides, the PSCA 76–84 peptide most effectively induced peptide-specific cytotoxic T lymphocytes (CTLs) from PBMCs of HLA-A24+ prostate cancer patients. Cytotoxicity was dependent on peptide-specific and CD8+ T cells. The PSCA 76–84 peptide-stimulated PBMCs showed a significant level of cytotoxicity against prostate cancer cells in an HLA-A24-restricted manner. IgG reactive to the PSCA 76–84 peptide was detected in half of patients. CONCLUSIONS The PSCA 76–84 peptide should be considered for use in clinical trials of immunotherapy for HLA-A24+ patients. © 2004 Wiley-Liss, Inc.

  • prostate specific antigen derived epitopes capable of inducing cellular and humoral responses in hla a24 prostate cancer patients
    The Prostate, 2003
    Co-Authors: Mamoru Harada, Satoko Matsueda, Kazuhiko Kobayashi, Masami Nakagawa, Masanori Noguchi, Kyogo Itoh
    Abstract:

    BACKGROUND We tried to identify prostate-specific antigen (PSA)-derived epitopes immunogenic in HLA-A24+ prostate cancer patients. METHODS Peripheral blood mononuclear cells (PBMCs) were in vitro stimulated with each of four different PSA peptides carrying the HLA-A24 binding motif, and their HLA-A24-restricted anti-tumor responses were examined using a parental HLA-A24-negative prostate cancer cell line (PC93) and its HLA-A24-expressing transfectant line (PC93-A24). Serum levels of immunoglobulin G (IgG) against PSA peptides were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS PBMCs, which were in vitro stimulated with either the PSA152–160 or PSA248–257 peptide, showed higher levels of IFN-γ production and cytotoxicity against the PC93-A24 than against the PC93. IgG against the PSA248–257 peptide was detected in half of the prostate cancer patients tested. CONCLUSIONS The PSA152–160 and PSA248–257 peptides could be appropriate target molecules in use for specific immunotherapy of HLA-A24+ prostate cancer patients. Prostate 57: 152–159, 2003. © 2003 Wiley-Liss, Inc.

Mamoru Harada - One of the best experts on this subject based on the ideXlab platform.

  • kinesin superfamily protein derived peptides with the ability to induce glioma reactive cytotoxic t lymphocytes in human leukocyte antigen a24 glioma patients
    Oncology Reports, 2007
    Co-Authors: Mamoru Harada, Kyogo Itoh, Yuki Ishihara, Ryuya Yamanaka
    Abstract:

    One promising modality in the treatment of malignant glioma is specific immunotherapy. However, this modality requires information about target antigens and their epitope peptides that are recognized by T cells. In this study, we searched for new target candidates in specific immunotherapy for malignant glioma by utilizing cDNA microarray technology to compare gene expressions in malignant glioma tissues to those in benign glioma and a panel of normal tissues. The selected genes included three members of the kinesin superfamily proteins (KIFs): KIF1C, KIF3C, and KIF21B. RT-PCR showed that these three genes were expressed in the majority of glioma cell lines. These antigen-derived 25 peptides, which had the ability to bind to human leukocyte antigen (HLA)-A24 molecules, were first screened for their ability to be recognized by the immunoglobulin G of glioma patients, and then tested for their potential to induce peptide-specific and glioma-reactive cytotoxic T lymphocytes (CTLs) from the peripheral blood mononuclear cells of HLA-A24 + glioma patients. The results showed that the KIF1C 149-198 and KIF3C 512-520 peptides efficiently induced HLA-A24-restricted and glioma-reactive CD8 + T cells. These results suggest the existence of KIF-reactive CTL precursors in glioma patients, and should facilitate the development of specific immunotherapies for malignant glioma.

  • identification of squamous cell carcinoma antigen derived peptides having the capacity of inducing cancer reactive ctls in hla a24 cancer patients
    International Journal of Oncology, 2006
    Co-Authors: Shigenori Homma, Mamoru Harada, Hirohisa Yano, Sachiko Ogasawara, Satoko Matsueda, Nobukazu Komatsu, Shigeki Shichijo, Hiroki Shomura, Yoshiaki Maeda, Yuji Sato
    Abstract:

    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 PCR. SCCA protein expression in cancer tissues was investigated by immunohistochemical staining. Thereafter, SCCA-derived peptide candidates were prepared based on their binding motifs to HLA-A24 molecules. Among these peptides, SCCA-derived peptides that were frequently recognized by humoral immunity were further tested for their ability to induce cancer-reactive cytotoxic T lymphocytes (CTLs) from the peripheral blood mononuclear cells of HLA-A24 + patients with SCC or non-SCC. As a result, the majority of SCC lines and tissues were positive for SCCA both at mRNA and protein levels. By contrast, non-SCC cancer tissues hardly expressed it at the protein level, although adenocarcinoma cell lines partly expressed it at the mRNA level. Four SCCA-derived peptides were frequently recognized by immunoglobulin G of both SCC and non-SCC cancer patients. Among these peptides, both the SCCA 112-120 and SCCA 215-224 peptides were found to effectively induce peptide-specific CTLs toward HLA-A24 + SCCA + cancer cells from the peripheral blood mononuclear cells of both SCC and non-SCC cancer patients. Two newly identified SCCA-derived peptides with the ability to induce CTL activity in both SCC and non-SCC cancer patients may be applicable to specific immunotherapy for HLA-A24 + cancer patients with SCC, but not those with non-SCC.

  • prostatic acid phosphatase as a target molecule in specific immunotherapy for patients with nonprostate adenocarcinoma
    Journal of Immunotherapy, 2005
    Co-Authors: Yi Wang, Mamoru Harada, Hirohisa Yano, Sachiko Ogasawara, Hiroko Takedatsu, Yoshimi Arima, Satoko Matsueda, Akira Yamada, Kyogo Itoh
    Abstract:

    Prostatic acid phosphatase (PAP) is one of the prostate-related antigens that are applicable to specific immunotherapy for patients with prostate cancer. In this study, we determined whether or not PAP could be a target molecule in specific immunotherapy for patients with nonprostate cancer. Avariety of adenocarcinoma cell lines were examined for their PAP expression at the mRNA and protein levels by reverse transcription polymerase chain reaction and western blot analysis, respectively. Considerable percentages of colon, gastric, and breast cancer cell lines were found to be positive for PAP at both the mRNA and the protein levels. The PAP expression in cancer tissues was also confirmed by immunohistochemical staining. In addition, we examined whether cancer-reactive cytotoxic T lymphocytes (CTLs) could be induced from peripheral blood mononuclear cells (PBMCs) of human leukocyte antigen (HLA) A24 + nonprostate cancer patients by in vitro stimulation with a PAP peptide. As a result, tumor-specific CTLs could be induced from the PBMCs of HLA-A24 + colon and gastric cancer patients. Their cytotoxicity against HLA-A24 + cancer cells was dependent on PAP peptide-specific and CD8 + T cells. These findings indicate that PAP could be a target molecule in specific immunotherapy for patients with nonprostate adenocarcinomas including colon and gastric cancers.

  • a prostate stem cell antigen derived peptide immunogenic in hla a24 prostate cancer patients
    The Prostate, 2004
    Co-Authors: Satoko Matsueda, Kyogo Itoh, Yuki Ishihara, Masanori Noguchi, Akihisa Yao, Rika Ogata, Mamoru Harada
    Abstract:

    BACKGROUND We attempted to identify prostate stem cell antigen (PSCA)-derived peptides immunogenic in HLA-A24+ prostate cancer patients. METHODS Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with each of three different PSCA-derived peptides, which were prepared based on the HLA-A24 binding motif, and their peptide-specific and HLA-A24-restricted anti-tumor responses were examined. Plasma levels of immunoglobulin G (IgG) against PSCA peptides were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Among three PSCA peptides, the PSCA 76–84 peptide most effectively induced peptide-specific cytotoxic T lymphocytes (CTLs) from PBMCs of HLA-A24+ prostate cancer patients. Cytotoxicity was dependent on peptide-specific and CD8+ T cells. The PSCA 76–84 peptide-stimulated PBMCs showed a significant level of cytotoxicity against prostate cancer cells in an HLA-A24-restricted manner. IgG reactive to the PSCA 76–84 peptide was detected in half of patients. CONCLUSIONS The PSCA 76–84 peptide should be considered for use in clinical trials of immunotherapy for HLA-A24+ patients. © 2004 Wiley-Liss, Inc.

  • prostate specific antigen derived epitopes capable of inducing cellular and humoral responses in hla a24 prostate cancer patients
    The Prostate, 2003
    Co-Authors: Mamoru Harada, Satoko Matsueda, Kazuhiko Kobayashi, Masami Nakagawa, Masanori Noguchi, Kyogo Itoh
    Abstract:

    BACKGROUND We tried to identify prostate-specific antigen (PSA)-derived epitopes immunogenic in HLA-A24+ prostate cancer patients. METHODS Peripheral blood mononuclear cells (PBMCs) were in vitro stimulated with each of four different PSA peptides carrying the HLA-A24 binding motif, and their HLA-A24-restricted anti-tumor responses were examined using a parental HLA-A24-negative prostate cancer cell line (PC93) and its HLA-A24-expressing transfectant line (PC93-A24). Serum levels of immunoglobulin G (IgG) against PSA peptides were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS PBMCs, which were in vitro stimulated with either the PSA152–160 or PSA248–257 peptide, showed higher levels of IFN-γ production and cytotoxicity against the PC93-A24 than against the PC93. IgG against the PSA248–257 peptide was detected in half of the prostate cancer patients tested. CONCLUSIONS The PSA152–160 and PSA248–257 peptides could be appropriate target molecules in use for specific immunotherapy of HLA-A24+ prostate cancer patients. Prostate 57: 152–159, 2003. © 2003 Wiley-Liss, Inc.

Yoshihiko Hirohashi - One of the best experts on this subject based on the ideXlab platform.

  • development of an artificial antibody specific for hla peptide complex derived from cancer stem like cell cancer initiating cell antigen dnajb8
    British Journal of Cancer, 2020
    Co-Authors: Hiroki Tadano, Tomohide Tsukahara, Emi Mizushima, Asuka Akamatsu, Kazue Watanabe, Iyori Nojima, Terufumi Kubo, Takayuki Kanaseki, Yoshihiko Hirohashi, Noriyuki Sato
    Abstract:

    Background Peptide-vaccination therapy targeting tumour-associated antigens can elicit immune responses, but cannot be used to eliminate large tumour burden. In this study, we developed a therapeutic single-chain variable-fragment (scFv) antibody that recognises the cancer stem-like cell/cancer-initiating cell (CSC/CIC) antigen, DNAJB8. Methods We screened scFv clones reacting with HLA-A24:20/DNAJB8-derived peptide (DNAJB8_143) complex using naive scFv phage-display libraries. Reactivity and affinity of scFv clones against the cognate antigen were quantified using FACS and surface plasmon resonance. Candidate scFv clones were engineered to human IgG1 (hIgG1) and T-cell-engaging bispecific antibody (CD3xJB8). Complement-dependent cytotoxicity (CDC) and bispecific antibody-dependent cellular cytotoxicity (BADCC) were assessed. Results scFv clones A10 and B10 were isolated after bio-panning. Both A10-hIgG1 and B10-hIgG1 reacted with DNAJB8-143 peptide-pulsed antigen-presenting cells and HLA-A24(+)/DNAJB8(+) renal cell carcinoma and osteosarcoma cell lines. A10-hIgG1 and B10-hIgG1 showed strong affinity with the cognate HLA/peptide complex (KD = 2.96 × 10-9 M and 5.04 × 10-9 M, respectively). A10-hIgG1 and B10-hIgG1 showed CDC against HLA-A24(+)/DNAJB8(+) cell lines. B10-(CD3xJB8) showed superior BADCC to A10-(CD3xJB8). Conclusion We isolated artificial scFv antibodies reactive to CSC/CIC antigen DNAJB8-derived peptide naturally present on renal cell carcinoma and sarcoma. Immunotherapy using these engineered antibodies could be promising.

  • hla a24 ligandome analysis of colon and lung cancer cells identifies a novel cancer testis antigen and a neoantigen that elicits specific and strong ctl responses
    OncoImmunology, 2017
    Co-Authors: Vitaly Kochin, Tomohide Tsukahara, Takayuki Kanaseki, Yoshihiko Hirohashi, Serina Tokita, Sho Miyamoto, Yosuke Shionoya, Yasuhiro Kikuchi, Daichi Morooka, Kazue Watanabe
    Abstract:

    This study focused on HLA-A24 and comprehensively analyzed the ligandome of colon and lung cancer cells without the use of MHC-binding in silico prediction algorithms. Affinity purification using the antibody specific to HLA-A24 followed by LC-MS/MS sequencing was used to detect peptides, which harbored the known characteristics of HLA-A24 peptides in terms of length and anchor motifs. Ligandome analysis demonstrated the natural presentation of two different types of novel tumor-associated antigens. The ligandome contained a peptide derived from SUV39H2, a gene found to be expressed in a variety of cancers but not in normal tissues (except for the testis). The SUV39H2 peptide is immunogenic and elicits cytotoxic CD8+ T-cell (CTL) responses against cancer cells and is thus a novel cancer-testis antigen. Moreover, we found that microsatellite instability (MSI)-colon cancer cells displayed a neoepitope with an amino-acid substitution, while microsatellite stable (MSS)-colon and lung cancer cells displayed its counterpart peptide without the substitution. Structure modeling of peptide-HLA-A24 complexes predicted that the mutated residue at P8 was accessible to T-cell receptors. The neoepitope readily elicited CTL responses, which discriminated it from its wild-type counterpart, and the CTLs exhibited considerably high cytotoxicity against MSS-colon cancer cells carrying the responsible gene mutation. The specific and strong CTL lysis observed in this study fosters our understanding of immune surveillance against neoantigens.

  • aberrant expression and potency as a cancer immunotherapy target of inhibitor of apoptosis protein family livin ml iap in lung cancer
    Clinical Cancer Research, 2005
    Co-Authors: Hiroyuki Hariu, Yoshihiko Hirohashi, Toshihiko Torigoe, Hiroko Asanuma, Midori Hariu, Yasuaki Tamura, Katsuyuki Aketa, Chika Nabeta, Katsuya Nakanishi, Kenjiro Kamiguchi
    Abstract:

    CD8+ CTLs have an essential role in immune response against tumor. Although an increasing number of tumor-associated antigens that can be recognized by CTLs have been identified from human tumors, a limited number of tumor-associated antigens is known in lung cancer. In addition, because some of them are expressed in noncancerous tissues, there exist limitations in their application to tumor immunotherapy. Livin/ML-IAP is one of recently identified inhibitor of apoptosis protein (IAP) family, which is overexpressed in melanoma cells. In this report, we show that Livin/ML-IAP is aberrantly expressed in many lung cancer cell lines and primary lung cancer tissues, whereas it is not detectable in normal tissues, including lung by reverse transcription-PCR methods. To identify HLA-A24-restricted T-cell epitopes of Livin/ML-IAP, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. It was revealed that Livin7 peptide (amino acid sequence, KWFPSCQFLL) had the highest affinity to HLA-A24. By stimulating peripheral blood lymphocytes of HLA-A24-positive lung cancer patients with Livin7 peptide in vitro , the peptide-specific CTLs were successfully induced from four of five patients with Livin/ML-IAP-positive lung cancer but not from any of four patients without Livin/ML-IAP expression in their cancer tissues. Furthermore, the CTLs induced by Livin7 peptide showed cytotoxicity against Livin/ML-IAP+ lung cancer cell lines in an HLA-A24-restricted manner. Our data suggest that Livin/ML-IAP may be an excellent target antigen in immunotherapy for lung cancer and Livin7 peptide may serve as a potent peptide vaccine for HLA-A*2402 +/Livin+ lung cancer patients.

  • identification of human antitumor cytotoxic t lymphocytes epitopes of recoverin a cancer associated retinopathy antigen possibly related with a better prognosis in a paraneoplastic syndrome
    European Journal of Immunology, 2001
    Co-Authors: Akiko Maeda, Yoshihiko Hirohashi, Hiroshi Ohguro, Tadao Maeda, Yuki Nabeta, Hiroeki Sahara, Yoshimasa Wada, Takashi Sato, Chyuns Yun, Yasuharu Nishimura
    Abstract:

    Cancer-associated retinopathy (CAR) is a rare paraneoplastic syndrome, and the recoverin-specific autoantibody is suggested to contribute to the pathogenesis of retinopathy, including apoptosis of retinal cells. Because it is known that CAR(+) cancer patients have a preferable prognosis, we hypothesized that aberrantly expressed recoverin in cancer cells can become a target of cytotoxic T lymphocytes (CTL). Here we tested nine recoverin-derived HLA-A24-binding peptides for their capacity to elicit antitumor CTL. We observed recoverin-specific CTL responses in two HLA-A24(+) CAR(+) cancer patients. In addition, the CTL responses were obtained from three of ten CAR(-) cancer patients and two of six healthy individuals. The CTL precursor frequency of CAR(+) cancer patients and that of CAR(-) cancer patients was higher than that of healthy individuals. Of nine recoverin peptides, R49 (QFQSIYAKF), R49.2 (QFQSIYAKFF), and R64 (AYAQHVFRSF) were discovered to induce the peptide-specific CTL. Taken together, our present data suggest that peripheral activation of recoverin-specific antitumor CTL is likely to contribute to the preferable prognosis of CAR(+) cancer patients. Moreover, in cases other than CAR(+) cancer patients, recoverin may offer the opportunity to design epitope-based immunotherapeutic approaches for treating HLA-A24(+) cancer patients with a recoverin-expressing tumor.

Takuya Tsunoda - One of the best experts on this subject based on the ideXlab platform.

  • identification of hla a24 restricted novel t cell epitope peptides derived from p cadherin and kinesin family member 20a
    BioMed Research International, 2012
    Co-Authors: Ryuji Osawa, Takuya Tsunoda, Sachiko Yoshimura, Tomohisa Watanabe, Kazuyoshi Takeda, Motoki Miyazawa, Masaji Tani, Hidewaki Nakagawa
    Abstract:

    We here identified human leukocyte antigen-(HLA-)A∗2402-restricted epitope peptides from Cadherin 3, type 1, P-cadherin (CDH3) and kinesin family member 20A (KIF20A) that were found to be specifically expressed in cancer cells through genome-wide expression profile analysis. CDH3-10-807 peptide and KIF20A-10-66 peptide successfully induced specific CTL clones, and these selectively responded to COS7 cells expressing both HLA-A∗2402 and respective protein while did not respond to parental cells or COS7 cells expressing either HLA-A∗2402 or respective protein. Furthermore, CTL clones responded to cancer cells that endogenously express HLA-A∗2402 and respective protein, suggesting that CDH3-10-807 peptide and KIF20A-10-66 peptide are naturally presented on HLA-A∗2402 molecule of human cancer cells. Our results demonstrated that CDH3-10-807 peptide and KIF20A-10-66 peptide are novel HLA-A24-restricted tumor-associated antigens and would be applicable for CTL-inducing cancer therapies.

  • identification of sparc as a candidate target antigen for immunotherapy of various cancers
    International Journal of Cancer, 2010
    Co-Authors: Mitsuhiro Inoue, Satoru Senju, Yoshiaki Ikuta, Michiko Harao, Shinya Hirata, Yuki Hayashida, Atsushi Irie, Katsunori Imai, Yusuke Tomita, Takuya Tsunoda
    Abstract:

    To establish efficient anticancer immunotherary, it is important to identify tumor-associated antigens (TAAs) directing the immune system to attack cancer. A genome-wide cDNA microarray analysis identified that secreted protein acidic and rich in cysteine (SPARC) gene is overexpressed in the gastric, pancreatic and colorectal cancer tissues but not in their noncancerous counterparts. This study attempted to identify HLA-A24 (A*2402)-restricted and SPARC-derived CTL epitopes. We previously identified H-2K(d)-restricted and SPARC-derived CTL epitope peptides in BALB/c mice, of which H-2K(d)-binding peptide motif is comparable with that of HLA-A24 binding peptides. By using these peptides, we tried to induce HLA-A24 (A*2402)-restricted and SPARC-reactive human CTLs and demonstrated an antitumor immune response. The SPARC-A24-1(143-151) (DYIGPCKYI) and SPARC-A24-4(225-234) (MYIFPVHWQF) peptides-reactive CTLs were successfully induced from peripheral blood mononuclear cells by in vitro stimulation with these two peptides in HLA-A24 (A*2402) positive healthy donors and cancer patients, and these CTLs exhibited cytotoxicity specific to cancer cells expressing both SPARC and HLA-A24 (A*2402). Furthermore, the adoptive transfer of the SPARC-specific CTLs could inhibit the tumor growth in nonobese diabetic/severe combined immunodeficient mice bearing human cancer cells expressing both HLA-A24 (A*2402) and SPARC. These findings suggest that SPARC is a potentially useful target candidate for cancer immunotherapy.

  • enhancement of cytotoxic t lymphocyte responses in patients with gastrointestinal malignancies following vaccination with cea peptide pulsed dendritic cells
    Cancer Immunology Immunotherapy, 2004
    Co-Authors: Kenji Matsuda, Takuya Tsunoda, H Tanaka, Hiroshi Tanimura, Ikuei Nukaya, Kazutoh Takesako, Yasukazu Umano, Hiroki Yamaue
    Abstract:

    Carcinoembryonic antigen (CEA) is strongly expressed in a vast majority of gastrointestinal carcinomas. Recently, epitope peptides of CEA were identified. We have demonstrated HLA-A24–restricted peptide, CEA652[9] (TYACFVSNL), was capable of eliciting specific cytotoxic T lymphocytes (CTLs) which could lyse tumor cells expressing HLA-A24 and CEA. HLA-A24 is the most applicable MHC class I allele in the Japanese population. In this pilot study, we have used the peptide-pulsed dendritic cells (DCs) generated from peripheral blood mononuclear cells (PBMCs) supplemented with GM-CSF and IL-4 as the source of the vaccine. Eight patients with advanced CEA-expressing gastrointestinal malignancies received subcutaneous injections every 2 or 3 weeks. Immunomonitoring was performed by ELISpot (enzyme-linked immunosorbent spot) assay to measure the precursor frequency of CTLs and their capacity to elicit antitumor CTLs in vitro. Four of seven patients have developed their CTL response after vaccinations. DTH reaction was observed in one of eight patients at the DC-injected site. Skin biopsy at the injected site showed the infiltration of the lymphocytes. Furthermore, A24/CEA peptide tetramer assay revealed an increase in peptide-specific T-cell precursor frequency in vaccinated patients. No significant toxic adverse effects were observed, except for mild diarrhea in one case after three vaccinations. Three patients have shown stabilization of the disease after vaccinations. In conclusion, our results clearly demonstrated that our vaccination protocol was safe and might develop a CEA-specific CTL response in cancer patients.

  • mapping the hla a24 restricted t cell epitope peptide from a tumour associated antigen her2 neu possible immunotherapy for colorectal carcinomas
    British Journal of Cancer, 2001
    Co-Authors: H Tanaka, Takuya Tsunoda, I Nukaya, A Sette, Kenji Matsuda, Y Umano, Hiroki Yamaue, K Takesako, Hiroshi Tanimura
    Abstract:

    HER2 / neu is a potential antigen candidate for immunotherapy because of its correlation to a poor prognosis and high expressions in many kinds of epithelial tumours. Especially in the colorectal carcinomas, the higher expression of HER2 / neu is recognized in metastatic regions as well as in primary sites. Several CTL epitopes restricted by HLA-A2.1 and -A3 were identified so far, however epitopes restricted by HLA-A24, that is one of the most common allele in Japanese and Caucasians, have not been identified. In this paper, we showed identification of a CTL epitope peptide of HER2 / neu restricted by HLA-A24. HLA-A24 binding peptides selected by an analysis based on HLA-A24 binding motifs were determined for their binding affinities to HLA-A24 molecules. The peptide with a sequence of RWGLLLALL (position 8–16) named HE1 showed the highest affinity. We induced CTLs from CD8+cells of HLA-A24 healthy donors by stimulation with HE1-pulsed autologous dendritic cells. The CTLs showed cytotoxic activity against not only the peptide-pulsed target cells but also HLA-A24 colorectal tumour cell lines that endogenously overexpressed HER2 / neu. The antigen-specificity was confirmed by cold target inhibition assay using HE1-pulsed target cells. In summary, HER2 / neu peptide, RWGLLLALL, may contribute to the induction of antitumour immunity with the peptide-based immunotherapy for the colorectal carcinomas. © 2001 Cancer Research Campaign http://www.bjcancer.com

Kazue Watanabe - One of the best experts on this subject based on the ideXlab platform.

  • development of an artificial antibody specific for hla peptide complex derived from cancer stem like cell cancer initiating cell antigen dnajb8
    British Journal of Cancer, 2020
    Co-Authors: Hiroki Tadano, Tomohide Tsukahara, Emi Mizushima, Asuka Akamatsu, Kazue Watanabe, Iyori Nojima, Terufumi Kubo, Takayuki Kanaseki, Yoshihiko Hirohashi, Noriyuki Sato
    Abstract:

    Background Peptide-vaccination therapy targeting tumour-associated antigens can elicit immune responses, but cannot be used to eliminate large tumour burden. In this study, we developed a therapeutic single-chain variable-fragment (scFv) antibody that recognises the cancer stem-like cell/cancer-initiating cell (CSC/CIC) antigen, DNAJB8. Methods We screened scFv clones reacting with HLA-A24:20/DNAJB8-derived peptide (DNAJB8_143) complex using naive scFv phage-display libraries. Reactivity and affinity of scFv clones against the cognate antigen were quantified using FACS and surface plasmon resonance. Candidate scFv clones were engineered to human IgG1 (hIgG1) and T-cell-engaging bispecific antibody (CD3xJB8). Complement-dependent cytotoxicity (CDC) and bispecific antibody-dependent cellular cytotoxicity (BADCC) were assessed. Results scFv clones A10 and B10 were isolated after bio-panning. Both A10-hIgG1 and B10-hIgG1 reacted with DNAJB8-143 peptide-pulsed antigen-presenting cells and HLA-A24(+)/DNAJB8(+) renal cell carcinoma and osteosarcoma cell lines. A10-hIgG1 and B10-hIgG1 showed strong affinity with the cognate HLA/peptide complex (KD = 2.96 × 10-9 M and 5.04 × 10-9 M, respectively). A10-hIgG1 and B10-hIgG1 showed CDC against HLA-A24(+)/DNAJB8(+) cell lines. B10-(CD3xJB8) showed superior BADCC to A10-(CD3xJB8). Conclusion We isolated artificial scFv antibodies reactive to CSC/CIC antigen DNAJB8-derived peptide naturally present on renal cell carcinoma and sarcoma. Immunotherapy using these engineered antibodies could be promising.

  • hla a24 ligandome analysis of colon and lung cancer cells identifies a novel cancer testis antigen and a neoantigen that elicits specific and strong ctl responses
    OncoImmunology, 2017
    Co-Authors: Vitaly Kochin, Tomohide Tsukahara, Takayuki Kanaseki, Yoshihiko Hirohashi, Serina Tokita, Sho Miyamoto, Yosuke Shionoya, Yasuhiro Kikuchi, Daichi Morooka, Kazue Watanabe
    Abstract:

    This study focused on HLA-A24 and comprehensively analyzed the ligandome of colon and lung cancer cells without the use of MHC-binding in silico prediction algorithms. Affinity purification using the antibody specific to HLA-A24 followed by LC-MS/MS sequencing was used to detect peptides, which harbored the known characteristics of HLA-A24 peptides in terms of length and anchor motifs. Ligandome analysis demonstrated the natural presentation of two different types of novel tumor-associated antigens. The ligandome contained a peptide derived from SUV39H2, a gene found to be expressed in a variety of cancers but not in normal tissues (except for the testis). The SUV39H2 peptide is immunogenic and elicits cytotoxic CD8+ T-cell (CTL) responses against cancer cells and is thus a novel cancer-testis antigen. Moreover, we found that microsatellite instability (MSI)-colon cancer cells displayed a neoepitope with an amino-acid substitution, while microsatellite stable (MSS)-colon and lung cancer cells displayed its counterpart peptide without the substitution. Structure modeling of peptide-HLA-A24 complexes predicted that the mutated residue at P8 was accessible to T-cell receptors. The neoepitope readily elicited CTL responses, which discriminated it from its wild-type counterpart, and the CTLs exhibited considerably high cytotoxicity against MSS-colon cancer cells carrying the responsible gene mutation. The specific and strong CTL lysis observed in this study fosters our understanding of immune surveillance against neoantigens.