The Experts below are selected from a list of 199542 Experts worldwide ranked by ideXlab platform
Takashi Nishimura - One of the best experts on this subject based on the ideXlab platform.
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local radiation therapy inhibits tumor growth through the generation of tumor specific ctl its potentiation by combination with Th1 Cell therapy
Cancer Research, 2010Co-Authors: Tsuguhide Takeshima, Kenji Chamoto, Daiko Wakita, Hiroki Shirato, Hidemitsu Kitamura, Takayuki Ohkuri, Yuji Togashi, Takashi NishimuraAbstract:Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8(+) T Cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer(+) tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 Cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 Cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL.
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local radiation therapy inhibits tumor growth through the generation of tumor specific ctl its potentiation by combination with Th1 Cell therapy
Cancer Research, 2010Co-Authors: Tsuguhide Takeshima, Kenji Chamoto, Daiko Wakita, Hiroki Shirato, Hidemitsu Kitamura, Takayuki Ohkuri, Yuji Togashi, Takashi NishimuraAbstract:Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8+ T Cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer+ tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 Cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 Cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL. Cancer Res; 70(7); 2697–706
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Abstract #LB-154: Identification of novel helper epitopes of MAGE-A4 and Survivin tumor antigen: Useful tool for the propagation of Th1 Cells
Cancer Research, 2009Co-Authors: Takayuki Ohkuri, Kenji Chamoto, Daiko Wakita, Hidemitsu Kitamura, Yuji Togashi, Daisuke Noguchi, Minoru Kobayashi, Kazutaka Masuko, Junya Ohtake, Takashi NishimuraAbstract:AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO MAGE-A4 has been considered as an attractive cancer-testis (CT) antigen for tumor immunotherapy. It has been well accepted that T helper type 1 (Th1)-dominant immunity is critical for the successful induction of antitumor immunity in a tumor-bearing host. The adoptive Th1 Cell therapy has been demonstrated to be an attractive strategy for inducing tumor eradication in mouse systems. However, no clinical trial of Th1 Cell therapy has carried out. Here, we first identified MAGE-A4-derived promiscuous helper epitope peptide bound to both HLA-DPB1*0501 and DRB1*1403. Using the peptide, we established a suitable protocol for the propagation of MAGE-A4-specific Th1 Cells in vitro. Culture of CD4+ T Cells with IFN-\#947;-treated peripheral blood mononuclear Cells (PBMC)-derived adherent Cells in the presence of helper epitope peptide resulted in a great expansion of MAGE-A4-reactive Th Cells producing IFN-\#947; but not IL-4. Moreover, it was demonstrated that ligation of MAGE-A4-reactive Th1 Cells with the cognate peptide caused the production of IFN-\#947; and IL-2. Using this expansion procedure, we identified two novel survivin helper peptides, SU21 and SU22. The survivin molecule is known as one of the most desired target molecules for tumor immunotherapy. Therefore, survivin-specific Th1 Cells would also play a critical role for tumor immunotherapy. Among the identified peptides, SU22 is capable of binding to HLA-DR53. The other peptide was presented to Th1 Cells by HLA-DRB1*1501/1502. The Th1 Cells induced by SU21 or SU22 produced IFN-\#947; against autologous dendritic Cells pulsed with recombinant survivin protein, suggesting that both epitopes are functional antigens, which are naturally processed and presented. When PBMC were cultured with activated survivin-reactive Th1 Cells in the presence of survivin peptide, most immunoregulatory Cells including CD8-, CD19-, CD56- and CD11c-positive Cells increased the expression levels of early activation maker, CD69. Moreover cytotoxic activity of NK Cells and CD8+ T Cells increased. It is suggesting that administration of activated Th1 Cells would promote activity of immune Cells in patients with cancer. Thus, our identified MAGE-A4 and survivin helper epitope peptides will become good tools for the propagation of tumor-specific Th1 Cells applicable to adoptive immunotherapy of human cancer. We are planning a clinical trial of Th1 Cell therapy combined with helper peptides after evaluating its rationality in hu-mouse therapy model. The new challenge to the adoptive immunotherapy is now started and we believed Th1 Cell therapy using tumor-specific Th1 Cells expanded with helper epitope peptide will become a promising strategy for the immunotherapy of human cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-154.
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Th1 Cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs.
International immunology, 2006Co-Authors: Yue Zhang, Kenji Chamoto, Daiko Wakita, Hidemitsu Kitamura, Yoshinori Narita, Naoki Matsubara, Takashi NishimuraAbstract:We have previously described a method for adoptive immunotherapy of cancer based on antigenspecific Th1 Cells. However, efficient induction of anti-tumor responses using Th1 Cells remains a formidable challenge, especially for MHC class II-negative tumors. In the present study, we sought to develop a novel strategy to eradicate established tumors of the MHC class II-negative, ovalbumin (OVA)-expressing EG-7 Cells. Tumor-bearing mice were intradermally treated with OVA-specific Th1 Cells, combined with the model tumor antigen (OVA), near the tumor-draining lymph node (DLN). We found that tumor growth was significantly inhibited by this strategy and ;50‐60% of tumor-bearing mice were completely cured. Tumor eradication was crucially dependent on the generation of OVA/ H-2K b -specific CTLs in the tumor DLNs and tumor site. The injected Th1 Cells were mainly distributed in tumor DLNs, where they vigorously proliferated and enhanced the activation of dendritic Cells. Strikingly, we also found that the accumulation of CD4 + CD25 + regulatory T Cells (Tregs) was significantly inhibited in tumor DLNs by Th1 Cell adjuvant therapy and this abrogation was associated with IFNg secreted by Th1 Cells. These results identify Th1 Cell adjuvant therapy combined with tumor vaccination as a novel approach to the treatment of human cancer.
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A novel tumor Cell therapy using Th1 Cells: The critical role of APC/Th1 Cell-Cell interaction for the initiation of antitumor immunity in vivo
Cancer Research, 2004Co-Authors: Takashi Nishimura, Kenji Chamoto, Takemasa TsujiAbstract:5451 The introduction of local help, which can overcome immunosuppression of tumor-bearing host, is essential for developing antigen-specific tumor immunotherapy. To introduce local help, we have investigated the adoptive tumor immunotherapy using Th1 Cells or Th1 cytokine-conditioned bone marrow-derived dendritic Cells (BMDC1). The adoptive transfer of OVA-specific Th1 Cells (over 2x107) into tumor-bearing mice caused a complete regression of tumor mass of A20-OVA which were A20 B lymphoma Cells transfected with OVA gene as a model tumor antigen. For successful Th1-Cell therapy, host CD8+T Cells were essential in addition to Th1 Cells. Thus, Th1/Tc1 circuit appears to be important for complete rejection of tumor by Th1 Cell therapy. To induce Th1-dominant antitumor immunity in A20-OVA-bearing mice, we also tried to apply OVA-pulsed BMDC1, which were preferable for inducing antigen-specific Th1 and Tc1 Cells, to adoptive tumor immunotherapy. Vaccination of A20-OVA-bearing mice with intradermal injection of inactivated A20-OVA, OVA pulsed-BMDC1 or Th1 Cells (5x106) alone showed no significant antitumor effect in vivo. However, combined vaccination therapy with OVA-pulsed BMDC1, A20-OVA and Th1 Cells caused a complete regression of tumor mass. Thus, Th1 Cells were demonstrated to augment BMDC1-based tumor vaccination therapy in vivo. Finally, we have succeeded to cure mice bearing with MHC class II-negative EG-7 tumor Cells using Th1-Cell therapy. Using this model, we demonstrated that APC/Th1 Cell-Cell interaction and Th1 Cell expansion in draininig lymph node is essential for the induction of tetramer-positive tumor specific CTL and complete regression of tumor. We also succeeded in generation of tumor-specific human Th1 Cells. Therefore, Th1-Cell therapy will provide a new strategy for tumor Cell therapy in future.
Kenji Chamoto - One of the best experts on this subject based on the ideXlab platform.
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local radiation therapy inhibits tumor growth through the generation of tumor specific ctl its potentiation by combination with Th1 Cell therapy
Cancer Research, 2010Co-Authors: Tsuguhide Takeshima, Kenji Chamoto, Daiko Wakita, Hiroki Shirato, Hidemitsu Kitamura, Takayuki Ohkuri, Yuji Togashi, Takashi NishimuraAbstract:Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8(+) T Cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer(+) tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 Cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 Cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL.
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local radiation therapy inhibits tumor growth through the generation of tumor specific ctl its potentiation by combination with Th1 Cell therapy
Cancer Research, 2010Co-Authors: Tsuguhide Takeshima, Kenji Chamoto, Daiko Wakita, Hiroki Shirato, Hidemitsu Kitamura, Takayuki Ohkuri, Yuji Togashi, Takashi NishimuraAbstract:Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8+ T Cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer+ tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 Cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 Cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL. Cancer Res; 70(7); 2697–706
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Abstract #LB-154: Identification of novel helper epitopes of MAGE-A4 and Survivin tumor antigen: Useful tool for the propagation of Th1 Cells
Cancer Research, 2009Co-Authors: Takayuki Ohkuri, Kenji Chamoto, Daiko Wakita, Hidemitsu Kitamura, Yuji Togashi, Daisuke Noguchi, Minoru Kobayashi, Kazutaka Masuko, Junya Ohtake, Takashi NishimuraAbstract:AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO MAGE-A4 has been considered as an attractive cancer-testis (CT) antigen for tumor immunotherapy. It has been well accepted that T helper type 1 (Th1)-dominant immunity is critical for the successful induction of antitumor immunity in a tumor-bearing host. The adoptive Th1 Cell therapy has been demonstrated to be an attractive strategy for inducing tumor eradication in mouse systems. However, no clinical trial of Th1 Cell therapy has carried out. Here, we first identified MAGE-A4-derived promiscuous helper epitope peptide bound to both HLA-DPB1*0501 and DRB1*1403. Using the peptide, we established a suitable protocol for the propagation of MAGE-A4-specific Th1 Cells in vitro. Culture of CD4+ T Cells with IFN-\#947;-treated peripheral blood mononuclear Cells (PBMC)-derived adherent Cells in the presence of helper epitope peptide resulted in a great expansion of MAGE-A4-reactive Th Cells producing IFN-\#947; but not IL-4. Moreover, it was demonstrated that ligation of MAGE-A4-reactive Th1 Cells with the cognate peptide caused the production of IFN-\#947; and IL-2. Using this expansion procedure, we identified two novel survivin helper peptides, SU21 and SU22. The survivin molecule is known as one of the most desired target molecules for tumor immunotherapy. Therefore, survivin-specific Th1 Cells would also play a critical role for tumor immunotherapy. Among the identified peptides, SU22 is capable of binding to HLA-DR53. The other peptide was presented to Th1 Cells by HLA-DRB1*1501/1502. The Th1 Cells induced by SU21 or SU22 produced IFN-\#947; against autologous dendritic Cells pulsed with recombinant survivin protein, suggesting that both epitopes are functional antigens, which are naturally processed and presented. When PBMC were cultured with activated survivin-reactive Th1 Cells in the presence of survivin peptide, most immunoregulatory Cells including CD8-, CD19-, CD56- and CD11c-positive Cells increased the expression levels of early activation maker, CD69. Moreover cytotoxic activity of NK Cells and CD8+ T Cells increased. It is suggesting that administration of activated Th1 Cells would promote activity of immune Cells in patients with cancer. Thus, our identified MAGE-A4 and survivin helper epitope peptides will become good tools for the propagation of tumor-specific Th1 Cells applicable to adoptive immunotherapy of human cancer. We are planning a clinical trial of Th1 Cell therapy combined with helper peptides after evaluating its rationality in hu-mouse therapy model. The new challenge to the adoptive immunotherapy is now started and we believed Th1 Cell therapy using tumor-specific Th1 Cells expanded with helper epitope peptide will become a promising strategy for the immunotherapy of human cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-154.
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Combination tumor immunotherapy with radiotherapy and Th1 Cell therapy against murine lung carcinoma
Clinical & experimental metastasis, 2007Co-Authors: Hiroshi Yokouchi, Kenji Chamoto, Daiko Wakita, Koichi Yamazaki, Hiroki Shirato, Tsuguhide Takeshima, Hirotoshi Dosaka-akita, Masaharu Nishimura, Zhang Yue, Hidemitsu KitamuraAbstract:Mice bearing established Lewis lung carcinoma (LLC) expressing model tumor antigen, ovalbumin (OVA) (LLC-OVA) marginally responded to local radiotherapy, but none of the mice was cured. In contrast, treatment of the tumor-bearing mice with intratumoral injection of tumor-specific T helper type 1 (Th1) Cells and tumor antigen (OVA) after radiotherapy dramatically prolonged the survival days and induced complete cure of the mice at high frequency (80%). Radiation therapy combined with Th1 Cells or OVA alone showed no significant therapeutic activity against LLC-OVA. Such a strong therapeutic activity was not induced by intratumoral injection of Th1 Cells plus OVA. Compared with other treatment, radiation therapy combined with Th1 Cells and OVA was superior to induce the generation of OVA/H-2(b) tetramer(+) tumor-specific cytotoxic T lymphocyte (CTL) with a strong cytotoxicity against LLC-OVA in draining lymph node (DLN). Moreover, the combined therapy is demonstrated to inhibit the growth of tumor mass, which grew at contralateral side. These results indicated that radiotherapy combined with Th1 Cell/vaccine therapy induced a systemic antitumor immunity. These findings suggested that combination therapy with radiotherapy and Th1 Cell/vaccine therapy may become a practical strategy for cancer treatment.
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Th1 Cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs.
International immunology, 2006Co-Authors: Yue Zhang, Kenji Chamoto, Daiko Wakita, Hidemitsu Kitamura, Yoshinori Narita, Naoki Matsubara, Takashi NishimuraAbstract:We have previously described a method for adoptive immunotherapy of cancer based on antigenspecific Th1 Cells. However, efficient induction of anti-tumor responses using Th1 Cells remains a formidable challenge, especially for MHC class II-negative tumors. In the present study, we sought to develop a novel strategy to eradicate established tumors of the MHC class II-negative, ovalbumin (OVA)-expressing EG-7 Cells. Tumor-bearing mice were intradermally treated with OVA-specific Th1 Cells, combined with the model tumor antigen (OVA), near the tumor-draining lymph node (DLN). We found that tumor growth was significantly inhibited by this strategy and ;50‐60% of tumor-bearing mice were completely cured. Tumor eradication was crucially dependent on the generation of OVA/ H-2K b -specific CTLs in the tumor DLNs and tumor site. The injected Th1 Cells were mainly distributed in tumor DLNs, where they vigorously proliferated and enhanced the activation of dendritic Cells. Strikingly, we also found that the accumulation of CD4 + CD25 + regulatory T Cells (Tregs) was significantly inhibited in tumor DLNs by Th1 Cell adjuvant therapy and this abrogation was associated with IFNg secreted by Th1 Cells. These results identify Th1 Cell adjuvant therapy combined with tumor vaccination as a novel approach to the treatment of human cancer.
Hidemitsu Kitamura - One of the best experts on this subject based on the ideXlab platform.
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local radiation therapy inhibits tumor growth through the generation of tumor specific ctl its potentiation by combination with Th1 Cell therapy
Cancer Research, 2010Co-Authors: Tsuguhide Takeshima, Kenji Chamoto, Daiko Wakita, Hiroki Shirato, Hidemitsu Kitamura, Takayuki Ohkuri, Yuji Togashi, Takashi NishimuraAbstract:Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8(+) T Cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer(+) tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 Cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 Cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL.
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local radiation therapy inhibits tumor growth through the generation of tumor specific ctl its potentiation by combination with Th1 Cell therapy
Cancer Research, 2010Co-Authors: Tsuguhide Takeshima, Kenji Chamoto, Daiko Wakita, Hiroki Shirato, Hidemitsu Kitamura, Takayuki Ohkuri, Yuji Togashi, Takashi NishimuraAbstract:Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8+ T Cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer+ tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 Cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 Cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL. Cancer Res; 70(7); 2697–706
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Abstract #LB-154: Identification of novel helper epitopes of MAGE-A4 and Survivin tumor antigen: Useful tool for the propagation of Th1 Cells
Cancer Research, 2009Co-Authors: Takayuki Ohkuri, Kenji Chamoto, Daiko Wakita, Hidemitsu Kitamura, Yuji Togashi, Daisuke Noguchi, Minoru Kobayashi, Kazutaka Masuko, Junya Ohtake, Takashi NishimuraAbstract:AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO MAGE-A4 has been considered as an attractive cancer-testis (CT) antigen for tumor immunotherapy. It has been well accepted that T helper type 1 (Th1)-dominant immunity is critical for the successful induction of antitumor immunity in a tumor-bearing host. The adoptive Th1 Cell therapy has been demonstrated to be an attractive strategy for inducing tumor eradication in mouse systems. However, no clinical trial of Th1 Cell therapy has carried out. Here, we first identified MAGE-A4-derived promiscuous helper epitope peptide bound to both HLA-DPB1*0501 and DRB1*1403. Using the peptide, we established a suitable protocol for the propagation of MAGE-A4-specific Th1 Cells in vitro. Culture of CD4+ T Cells with IFN-\#947;-treated peripheral blood mononuclear Cells (PBMC)-derived adherent Cells in the presence of helper epitope peptide resulted in a great expansion of MAGE-A4-reactive Th Cells producing IFN-\#947; but not IL-4. Moreover, it was demonstrated that ligation of MAGE-A4-reactive Th1 Cells with the cognate peptide caused the production of IFN-\#947; and IL-2. Using this expansion procedure, we identified two novel survivin helper peptides, SU21 and SU22. The survivin molecule is known as one of the most desired target molecules for tumor immunotherapy. Therefore, survivin-specific Th1 Cells would also play a critical role for tumor immunotherapy. Among the identified peptides, SU22 is capable of binding to HLA-DR53. The other peptide was presented to Th1 Cells by HLA-DRB1*1501/1502. The Th1 Cells induced by SU21 or SU22 produced IFN-\#947; against autologous dendritic Cells pulsed with recombinant survivin protein, suggesting that both epitopes are functional antigens, which are naturally processed and presented. When PBMC were cultured with activated survivin-reactive Th1 Cells in the presence of survivin peptide, most immunoregulatory Cells including CD8-, CD19-, CD56- and CD11c-positive Cells increased the expression levels of early activation maker, CD69. Moreover cytotoxic activity of NK Cells and CD8+ T Cells increased. It is suggesting that administration of activated Th1 Cells would promote activity of immune Cells in patients with cancer. Thus, our identified MAGE-A4 and survivin helper epitope peptides will become good tools for the propagation of tumor-specific Th1 Cells applicable to adoptive immunotherapy of human cancer. We are planning a clinical trial of Th1 Cell therapy combined with helper peptides after evaluating its rationality in hu-mouse therapy model. The new challenge to the adoptive immunotherapy is now started and we believed Th1 Cell therapy using tumor-specific Th1 Cells expanded with helper epitope peptide will become a promising strategy for the immunotherapy of human cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-154.
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Combination tumor immunotherapy with radiotherapy and Th1 Cell therapy against murine lung carcinoma
Clinical & experimental metastasis, 2007Co-Authors: Hiroshi Yokouchi, Kenji Chamoto, Daiko Wakita, Koichi Yamazaki, Hiroki Shirato, Tsuguhide Takeshima, Hirotoshi Dosaka-akita, Masaharu Nishimura, Zhang Yue, Hidemitsu KitamuraAbstract:Mice bearing established Lewis lung carcinoma (LLC) expressing model tumor antigen, ovalbumin (OVA) (LLC-OVA) marginally responded to local radiotherapy, but none of the mice was cured. In contrast, treatment of the tumor-bearing mice with intratumoral injection of tumor-specific T helper type 1 (Th1) Cells and tumor antigen (OVA) after radiotherapy dramatically prolonged the survival days and induced complete cure of the mice at high frequency (80%). Radiation therapy combined with Th1 Cells or OVA alone showed no significant therapeutic activity against LLC-OVA. Such a strong therapeutic activity was not induced by intratumoral injection of Th1 Cells plus OVA. Compared with other treatment, radiation therapy combined with Th1 Cells and OVA was superior to induce the generation of OVA/H-2(b) tetramer(+) tumor-specific cytotoxic T lymphocyte (CTL) with a strong cytotoxicity against LLC-OVA in draining lymph node (DLN). Moreover, the combined therapy is demonstrated to inhibit the growth of tumor mass, which grew at contralateral side. These results indicated that radiotherapy combined with Th1 Cell/vaccine therapy induced a systemic antitumor immunity. These findings suggested that combination therapy with radiotherapy and Th1 Cell/vaccine therapy may become a practical strategy for cancer treatment.
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Th1 Cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs.
International immunology, 2006Co-Authors: Yue Zhang, Kenji Chamoto, Daiko Wakita, Hidemitsu Kitamura, Yoshinori Narita, Naoki Matsubara, Takashi NishimuraAbstract:We have previously described a method for adoptive immunotherapy of cancer based on antigenspecific Th1 Cells. However, efficient induction of anti-tumor responses using Th1 Cells remains a formidable challenge, especially for MHC class II-negative tumors. In the present study, we sought to develop a novel strategy to eradicate established tumors of the MHC class II-negative, ovalbumin (OVA)-expressing EG-7 Cells. Tumor-bearing mice were intradermally treated with OVA-specific Th1 Cells, combined with the model tumor antigen (OVA), near the tumor-draining lymph node (DLN). We found that tumor growth was significantly inhibited by this strategy and ;50‐60% of tumor-bearing mice were completely cured. Tumor eradication was crucially dependent on the generation of OVA/ H-2K b -specific CTLs in the tumor DLNs and tumor site. The injected Th1 Cells were mainly distributed in tumor DLNs, where they vigorously proliferated and enhanced the activation of dendritic Cells. Strikingly, we also found that the accumulation of CD4 + CD25 + regulatory T Cells (Tregs) was significantly inhibited in tumor DLNs by Th1 Cell adjuvant therapy and this abrogation was associated with IFNg secreted by Th1 Cells. These results identify Th1 Cell adjuvant therapy combined with tumor vaccination as a novel approach to the treatment of human cancer.
Daiko Wakita - One of the best experts on this subject based on the ideXlab platform.
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local radiation therapy inhibits tumor growth through the generation of tumor specific ctl its potentiation by combination with Th1 Cell therapy
Cancer Research, 2010Co-Authors: Tsuguhide Takeshima, Kenji Chamoto, Daiko Wakita, Hiroki Shirato, Hidemitsu Kitamura, Takayuki Ohkuri, Yuji Togashi, Takashi NishimuraAbstract:Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8(+) T Cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer(+) tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 Cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 Cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL.
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local radiation therapy inhibits tumor growth through the generation of tumor specific ctl its potentiation by combination with Th1 Cell therapy
Cancer Research, 2010Co-Authors: Tsuguhide Takeshima, Kenji Chamoto, Daiko Wakita, Hiroki Shirato, Hidemitsu Kitamura, Takayuki Ohkuri, Yuji Togashi, Takashi NishimuraAbstract:Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8+ T Cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer+ tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 Cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 Cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL. Cancer Res; 70(7); 2697–706
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Abstract #LB-154: Identification of novel helper epitopes of MAGE-A4 and Survivin tumor antigen: Useful tool for the propagation of Th1 Cells
Cancer Research, 2009Co-Authors: Takayuki Ohkuri, Kenji Chamoto, Daiko Wakita, Hidemitsu Kitamura, Yuji Togashi, Daisuke Noguchi, Minoru Kobayashi, Kazutaka Masuko, Junya Ohtake, Takashi NishimuraAbstract:AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO MAGE-A4 has been considered as an attractive cancer-testis (CT) antigen for tumor immunotherapy. It has been well accepted that T helper type 1 (Th1)-dominant immunity is critical for the successful induction of antitumor immunity in a tumor-bearing host. The adoptive Th1 Cell therapy has been demonstrated to be an attractive strategy for inducing tumor eradication in mouse systems. However, no clinical trial of Th1 Cell therapy has carried out. Here, we first identified MAGE-A4-derived promiscuous helper epitope peptide bound to both HLA-DPB1*0501 and DRB1*1403. Using the peptide, we established a suitable protocol for the propagation of MAGE-A4-specific Th1 Cells in vitro. Culture of CD4+ T Cells with IFN-\#947;-treated peripheral blood mononuclear Cells (PBMC)-derived adherent Cells in the presence of helper epitope peptide resulted in a great expansion of MAGE-A4-reactive Th Cells producing IFN-\#947; but not IL-4. Moreover, it was demonstrated that ligation of MAGE-A4-reactive Th1 Cells with the cognate peptide caused the production of IFN-\#947; and IL-2. Using this expansion procedure, we identified two novel survivin helper peptides, SU21 and SU22. The survivin molecule is known as one of the most desired target molecules for tumor immunotherapy. Therefore, survivin-specific Th1 Cells would also play a critical role for tumor immunotherapy. Among the identified peptides, SU22 is capable of binding to HLA-DR53. The other peptide was presented to Th1 Cells by HLA-DRB1*1501/1502. The Th1 Cells induced by SU21 or SU22 produced IFN-\#947; against autologous dendritic Cells pulsed with recombinant survivin protein, suggesting that both epitopes are functional antigens, which are naturally processed and presented. When PBMC were cultured with activated survivin-reactive Th1 Cells in the presence of survivin peptide, most immunoregulatory Cells including CD8-, CD19-, CD56- and CD11c-positive Cells increased the expression levels of early activation maker, CD69. Moreover cytotoxic activity of NK Cells and CD8+ T Cells increased. It is suggesting that administration of activated Th1 Cells would promote activity of immune Cells in patients with cancer. Thus, our identified MAGE-A4 and survivin helper epitope peptides will become good tools for the propagation of tumor-specific Th1 Cells applicable to adoptive immunotherapy of human cancer. We are planning a clinical trial of Th1 Cell therapy combined with helper peptides after evaluating its rationality in hu-mouse therapy model. The new challenge to the adoptive immunotherapy is now started and we believed Th1 Cell therapy using tumor-specific Th1 Cells expanded with helper epitope peptide will become a promising strategy for the immunotherapy of human cancer. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-154.
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Combination tumor immunotherapy with radiotherapy and Th1 Cell therapy against murine lung carcinoma
Clinical & experimental metastasis, 2007Co-Authors: Hiroshi Yokouchi, Kenji Chamoto, Daiko Wakita, Koichi Yamazaki, Hiroki Shirato, Tsuguhide Takeshima, Hirotoshi Dosaka-akita, Masaharu Nishimura, Zhang Yue, Hidemitsu KitamuraAbstract:Mice bearing established Lewis lung carcinoma (LLC) expressing model tumor antigen, ovalbumin (OVA) (LLC-OVA) marginally responded to local radiotherapy, but none of the mice was cured. In contrast, treatment of the tumor-bearing mice with intratumoral injection of tumor-specific T helper type 1 (Th1) Cells and tumor antigen (OVA) after radiotherapy dramatically prolonged the survival days and induced complete cure of the mice at high frequency (80%). Radiation therapy combined with Th1 Cells or OVA alone showed no significant therapeutic activity against LLC-OVA. Such a strong therapeutic activity was not induced by intratumoral injection of Th1 Cells plus OVA. Compared with other treatment, radiation therapy combined with Th1 Cells and OVA was superior to induce the generation of OVA/H-2(b) tetramer(+) tumor-specific cytotoxic T lymphocyte (CTL) with a strong cytotoxicity against LLC-OVA in draining lymph node (DLN). Moreover, the combined therapy is demonstrated to inhibit the growth of tumor mass, which grew at contralateral side. These results indicated that radiotherapy combined with Th1 Cell/vaccine therapy induced a systemic antitumor immunity. These findings suggested that combination therapy with radiotherapy and Th1 Cell/vaccine therapy may become a practical strategy for cancer treatment.
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Th1 Cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs.
International immunology, 2006Co-Authors: Yue Zhang, Kenji Chamoto, Daiko Wakita, Hidemitsu Kitamura, Yoshinori Narita, Naoki Matsubara, Takashi NishimuraAbstract:We have previously described a method for adoptive immunotherapy of cancer based on antigenspecific Th1 Cells. However, efficient induction of anti-tumor responses using Th1 Cells remains a formidable challenge, especially for MHC class II-negative tumors. In the present study, we sought to develop a novel strategy to eradicate established tumors of the MHC class II-negative, ovalbumin (OVA)-expressing EG-7 Cells. Tumor-bearing mice were intradermally treated with OVA-specific Th1 Cells, combined with the model tumor antigen (OVA), near the tumor-draining lymph node (DLN). We found that tumor growth was significantly inhibited by this strategy and ;50‐60% of tumor-bearing mice were completely cured. Tumor eradication was crucially dependent on the generation of OVA/ H-2K b -specific CTLs in the tumor DLNs and tumor site. The injected Th1 Cells were mainly distributed in tumor DLNs, where they vigorously proliferated and enhanced the activation of dendritic Cells. Strikingly, we also found that the accumulation of CD4 + CD25 + regulatory T Cells (Tregs) was significantly inhibited in tumor DLNs by Th1 Cell adjuvant therapy and this abrogation was associated with IFNg secreted by Th1 Cells. These results identify Th1 Cell adjuvant therapy combined with tumor vaccination as a novel approach to the treatment of human cancer.
Tsuguhide Takeshima - One of the best experts on this subject based on the ideXlab platform.
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local radiation therapy inhibits tumor growth through the generation of tumor specific ctl its potentiation by combination with Th1 Cell therapy
Cancer Research, 2010Co-Authors: Tsuguhide Takeshima, Kenji Chamoto, Daiko Wakita, Hiroki Shirato, Hidemitsu Kitamura, Takayuki Ohkuri, Yuji Togashi, Takashi NishimuraAbstract:Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8+ T Cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer+ tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 Cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 Cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL. Cancer Res; 70(7); 2697–706
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local radiation therapy inhibits tumor growth through the generation of tumor specific ctl its potentiation by combination with Th1 Cell therapy
Cancer Research, 2010Co-Authors: Tsuguhide Takeshima, Kenji Chamoto, Daiko Wakita, Hiroki Shirato, Hidemitsu Kitamura, Takayuki Ohkuri, Yuji Togashi, Takashi NishimuraAbstract:Radiation therapy is one of the primary treatment modalities for cancer along with chemotherapy and surgical therapy. The main mechanism of the tumor reduction after irradiation has been considered to be damage to the tumor DNA. However, we found that tumor-specific CTL, which were induced in the draining lymph nodes (DLN) and tumor tissue of tumor-bearing mice, play a crucial role in the inhibition of tumor growth by radiation. Indeed, the therapeutic effect of irradiation was almost completely abolished in tumor-bearing mice by depleting CD8(+) T Cells through anti-CD8 monoclonal antibody administration. In mice whose DLN were surgically ablated or genetically defective (Aly/Aly mice), the generation of tetramer(+) tumor-specific CTL at the tumor site was greatly reduced in parallel with the attenuation of the radiation-induced therapeutic effect against the tumor. This indicates that DLN are essential for the activation and accumulation of radiation-induced CTL, which are essential for inhibition of the tumor. A combined therapy of local radiation with Th1 Cell therapy augmented the generation of tumor-specific CTL at the tumor site and induced a complete regression of the tumor, although radiation therapy alone did not exhibit such a pronounced therapeutic effect. Thus, we conclude that the combination treatment of local radiation therapy and Th1 Cell therapy is a rational strategy to augment antitumor activity mediated by tumor-specific CTL.
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Combination tumor immunotherapy with radiotherapy and Th1 Cell therapy against murine lung carcinoma
Clinical & experimental metastasis, 2007Co-Authors: Hiroshi Yokouchi, Kenji Chamoto, Daiko Wakita, Koichi Yamazaki, Hiroki Shirato, Tsuguhide Takeshima, Hirotoshi Dosaka-akita, Masaharu Nishimura, Zhang Yue, Hidemitsu KitamuraAbstract:Mice bearing established Lewis lung carcinoma (LLC) expressing model tumor antigen, ovalbumin (OVA) (LLC-OVA) marginally responded to local radiotherapy, but none of the mice was cured. In contrast, treatment of the tumor-bearing mice with intratumoral injection of tumor-specific T helper type 1 (Th1) Cells and tumor antigen (OVA) after radiotherapy dramatically prolonged the survival days and induced complete cure of the mice at high frequency (80%). Radiation therapy combined with Th1 Cells or OVA alone showed no significant therapeutic activity against LLC-OVA. Such a strong therapeutic activity was not induced by intratumoral injection of Th1 Cells plus OVA. Compared with other treatment, radiation therapy combined with Th1 Cells and OVA was superior to induce the generation of OVA/H-2(b) tetramer(+) tumor-specific cytotoxic T lymphocyte (CTL) with a strong cytotoxicity against LLC-OVA in draining lymph node (DLN). Moreover, the combined therapy is demonstrated to inhibit the growth of tumor mass, which grew at contralateral side. These results indicated that radiotherapy combined with Th1 Cell/vaccine therapy induced a systemic antitumor immunity. These findings suggested that combination therapy with radiotherapy and Th1 Cell/vaccine therapy may become a practical strategy for cancer treatment.
