Objective： To investigate the antitumor effect of dendritic cell （DC） modified by gp96-peptide complexes both in vitro and in vivo. Methods：Gp96-peptide complexes were acquired from H22 liver cancer cells in mice....Objective： To investigate the antitumor effect of dendritic cell （DC） modified by gp96-peptide complexes both in vitro and in vivo. Methods：Gp96-peptide complexes were acquired from H22 liver cancer cells in mice. DC were cultured from bone marrow cells and modified by gp96-peptide complexes. Spleen lymphocytes of mice were activated by modified DC and the cytotoxicity were detected by ^51Cr release method. Modified DC, gp96-peptide complexes and inactivated H22 cells were injected into mice bearing H22 liver cancer cells to observe the levels of IL-10, IFN-y in serum and the alteration of proportions of CD8^＋-IFNy^＋ and CD8^＋-IL-10^＋ cells, CD4^＋-IFNy^＋ and CD4^＋-IL-10^＋ cells. Results： DC modified by gp96-peptide complexes can activate spleen lymphocyte and the latter can specifically kill H22 cells but not Ehrilich ascites carcinoma cells. Modified DC can improve the host＇s antitumor immune response and the proportions of Thl cells, inhibiting tumor growth. Conclusion： Gp96-peptide complexes can activate DC effectively, making DC a good vaccine.展开更多
Objective： To improve DC-based tumor vaccination, we studied whether dendritic ceils （DCs） which cocultured with H22 liver cancer cells-derived heat shock protein （HSP） glycoprotein 96 （gp96） affect the T cell-...Objective： To improve DC-based tumor vaccination, we studied whether dendritic ceils （DCs） which cocultured with H22 liver cancer cells-derived heat shock protein （HSP） glycoprotein 96 （gp96） affect the T cell-activating potential in vitro and the induction of tumor immunity in vivo. Methods： Maturation of murine bone marrow-derived DC was induced by GM-CSF plus IL-4, which mimiced the immunostimulatory effect of DC. Cocultured DC and gp96-peptide complexes were used to vaccine H22 liver cancer cells of mice. Using murine models we compared the immunogenecity of DC modified by gp96-peptides complexes derived from murine liver cancer cells alone or inactive tumor cells. To verify the specificity of the vaccine, in vitro assays were executed. Serum cytokine levels were quantified to explore the supposed pathway of DC modified by gp96 peptide complexes and its effect on antitumor immune response. Results： DC modified by gp96-peptide complexes can activate spleen lymphocyte and the latter can specifically kill H22 cells but not Ehrilich ascites carcinoma cells. Modified DC can induce potent tumor-antigenspecific immune response, augment the proliferation of Thl cells, and inhibit tumor growth. Conclusion： In this study, we have developed a novel DC-mediated tumor vaccine by combing the gp96 antigenic peptides complexes and inducing immune response against specific tumor cells, gp96 can be identified as a potent DC activator.展开更多
Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a firs...Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a first in man phase I study, we now report the results of therapeutic vaccination of non-small cell lung cancer (NSCLC) patients with an established, allogeneic non-small cell lung adenocarcinoma cell line secreting gp96-Ig. Advanced NSCLC-patients stage IIIB or IV of any histological subtype were enrolled and treated with up to 36 vaccinations over the course of 18 weeks. Primary endpoint was safety, secondary endpoints tumor response and overall survival. Measurement of tumor antigen specific CD8 CTL responses is precluded by the lack of known NSCLC associated antigens. Therefore, we measured patient CD8 T cell-IFN-γ responses to allo-antigens of the vaccine cells as surrogate for tumor antigen specific CD8 CTL. In 7 of 18 treated patients tumor growth was stabilized, however none of the 18 patients had an objective tumor response by RECIST criteria. Of 15 patients evaluable for immune response, 11 responded to vaccination with more than twofold increase in CD8-IFN-γ frequency above baseline. These patients had a median survival time of 16.5 months. Four patients who had no CD8 response above base line had survival times from 2.1 to 6.7 months. Our data are consistent with the concept that generation of CD8 CTL by therapeutic vaccination may delay tumor growth and progression and mediate prolonged survival even in the absence of objective tumor responses. Further studies will be required to test this concept and promising result.展开更多
基金Supported by National Natural Science Foundation of Chi-na (NO.30200369)
文摘Objective： To investigate the antitumor effect of dendritic cell （DC） modified by gp96-peptide complexes both in vitro and in vivo. Methods：Gp96-peptide complexes were acquired from H22 liver cancer cells in mice. DC were cultured from bone marrow cells and modified by gp96-peptide complexes. Spleen lymphocytes of mice were activated by modified DC and the cytotoxicity were detected by ^51Cr release method. Modified DC, gp96-peptide complexes and inactivated H22 cells were injected into mice bearing H22 liver cancer cells to observe the levels of IL-10, IFN-y in serum and the alteration of proportions of CD8^＋-IFNy^＋ and CD8^＋-IL-10^＋ cells, CD4^＋-IFNy^＋ and CD4^＋-IL-10^＋ cells. Results： DC modified by gp96-peptide complexes can activate spleen lymphocyte and the latter can specifically kill H22 cells but not Ehrilich ascites carcinoma cells. Modified DC can improve the host＇s antitumor immune response and the proportions of Thl cells, inhibiting tumor growth. Conclusion： Gp96-peptide complexes can activate DC effectively, making DC a good vaccine.
基金Supported by the National Natural Science Foundation of China (No. 30200369)
文摘Objective： To improve DC-based tumor vaccination, we studied whether dendritic ceils （DCs） which cocultured with H22 liver cancer cells-derived heat shock protein （HSP） glycoprotein 96 （gp96） affect the T cell-activating potential in vitro and the induction of tumor immunity in vivo. Methods： Maturation of murine bone marrow-derived DC was induced by GM-CSF plus IL-4, which mimiced the immunostimulatory effect of DC. Cocultured DC and gp96-peptide complexes were used to vaccine H22 liver cancer cells of mice. Using murine models we compared the immunogenecity of DC modified by gp96-peptides complexes derived from murine liver cancer cells alone or inactive tumor cells. To verify the specificity of the vaccine, in vitro assays were executed. Serum cytokine levels were quantified to explore the supposed pathway of DC modified by gp96 peptide complexes and its effect on antitumor immune response. Results： DC modified by gp96-peptide complexes can activate spleen lymphocyte and the latter can specifically kill H22 cells but not Ehrilich ascites carcinoma cells. Modified DC can induce potent tumor-antigenspecific immune response, augment the proliferation of Thl cells, and inhibit tumor growth. Conclusion： In this study, we have developed a novel DC-mediated tumor vaccine by combing the gp96 antigenic peptides complexes and inducing immune response against specific tumor cells, gp96 can be identified as a potent DC activator.
文摘Antigen containing, allogeneic cells secreting the genetically modified protein and peptide-chaperone gp96-Ig cross, prime and expand antigen specific CD8 T cells with therapeutic antitumor activity in mice. In a first in man phase I study, we now report the results of therapeutic vaccination of non-small cell lung cancer (NSCLC) patients with an established, allogeneic non-small cell lung adenocarcinoma cell line secreting gp96-Ig. Advanced NSCLC-patients stage IIIB or IV of any histological subtype were enrolled and treated with up to 36 vaccinations over the course of 18 weeks. Primary endpoint was safety, secondary endpoints tumor response and overall survival. Measurement of tumor antigen specific CD8 CTL responses is precluded by the lack of known NSCLC associated antigens. Therefore, we measured patient CD8 T cell-IFN-γ responses to allo-antigens of the vaccine cells as surrogate for tumor antigen specific CD8 CTL. In 7 of 18 treated patients tumor growth was stabilized, however none of the 18 patients had an objective tumor response by RECIST criteria. Of 15 patients evaluable for immune response, 11 responded to vaccination with more than twofold increase in CD8-IFN-γ frequency above baseline. These patients had a median survival time of 16.5 months. Four patients who had no CD8 response above base line had survival times from 2.1 to 6.7 months. Our data are consistent with the concept that generation of CD8 CTL by therapeutic vaccination may delay tumor growth and progression and mediate prolonged survival even in the absence of objective tumor responses. Further studies will be required to test this concept and promising result.
