BACKGROUND Hepatocellular carcinoma(HCC) has been revealed as the second most common cause of cancer-related deaths worldwide. The introduction of cell-based immunotherapy, including dendritic cells(DCs) and cytokine-...BACKGROUND Hepatocellular carcinoma(HCC) has been revealed as the second most common cause of cancer-related deaths worldwide. The introduction of cell-based immunotherapy, including dendritic cells(DCs) and cytokine-induced killer cells(CIKs), has brought HCC patients an effective benefit. However, the efficacy and necessity of cellular immunotherapy after different interventional therapy remains to be further explored.AIM To investigate the efficacy of cellular immunotherapy, involving DCs and CIKs,combined with different conventional treatments of HCC.METHODS We performed a literature search on PubMed and Web of Science up to February15, 2019. Long-term efficacy(overall survival and recurrence) and short-term adverse effects were investigated to assess the effectiveness of immunotherapy with DCs and/or CIKs. Review Manager 5.3 was used to perform the analysis.RESULTS A total of 22 studies involving 3756 patients selected by eligibility inclusion criteria were forwarded for meta-analysis. Combined with the conventional clinical treatment, immunotherapy with DCs and/or CIKs was demonstrated to significantly improve overall survival at 6 mo [risk ratio(RR) = 1.07;95%confidence interval(CI): 1.01-1.13, P = 0.02], 1 year(RR = 1.12;95%CI: 1.07-1.17, P< 0.00001), 3 years(RR = 1.23;95%CI: 1.15-1.31, P < 0.00001) and 5 years(RR =1.26;95%CI: 1.15-1.37, P < 0.00001). Recurrence rate was significantly reduced by cellular immunotherapy at 6 mo(RR = 0.50;95%CI: 0.36-0.69, P < 0.0001) and 1 year(RR = 0.82;95%CI: 0.75-0.89, P < 0.00001). Adverse effect assessment addressed that immunotherapy with DCs and/or CIKs was accepted as a safe,feasible treatment.CONCLUSION Combination immunotherapy with DCs, CIKs and DC/CIK with various routine treatments for HCC was evidently suggested to improve patients’ prognosis by increasing overall survival and reducing cancer recurrence.展开更多
AIM： To evaluate the safety and clinical efficacy of a new immunotherapy using both α-Gal epitope-pulsed dendritic cells （DCs） and cytokine-induced killer cells. METHODS： Freshly collected hepatocellular carcino...AIM： To evaluate the safety and clinical efficacy of a new immunotherapy using both α-Gal epitope-pulsed dendritic cells （DCs） and cytokine-induced killer cells. METHODS： Freshly collected hepatocellular carcinoma （HCC） tumor tissues were incubated with a mixture of neuraminidase and recombinant αl,3-galactosyltrans- ferase （αI,3GT） to synthesize α-Gal epitopes on car- bohydrate chains of the glycoproteins of tumor mem- branes. The subsequent incubation of the processed membranes in the presence of human natural anti-Gal IgG resulted in the effective phagocytosis to the tumor membrane by DCs. Eighteen patients aged 38-78 years with stage 111 primary HCC were randomly chosen for the study; 9 patients served as controls, and 9 patients were enrolled in the study group.RESULTS： The evaluation demonstrated that the pro- cedure was safe; no serious side effects or autoimmune diseases were observed. The therapy significantly pro- longed the survival of treated patients as compared with the controls （17.1 ± 2.01 mo vs 10.1 ±4.5 mo, P = 0.00121）. After treatment, all patients in the study group had positive delayed hypersensitivity and robust systemic cytotoxicity in response to tumor lysate as measured by interferon-y-expression in peripheral blood mononuclear cells using enzyme-linked immunosorbent spot assay. They also displayed increased numbers of CD8-, CD45RO- and CD56-positive cells in the peripheral blood and decreased α-fetoprotein level in the se- rum. CONCLUSION： This new tumor-specific immunotherapy is safe, effective and has a great potential for the treat- ment of tumors.展开更多
Background It remains a challenge to inhibit the local recurrence or distant metastasis of localized or locally advanced renal cell carcinoma （RCC） after surgical resection. We investigated the feasibility, safety a...Background It remains a challenge to inhibit the local recurrence or distant metastasis of localized or locally advanced renal cell carcinoma （RCC） after surgical resection. We investigated the feasibility, safety and efficacy of immunotherapy using autologous tumor lysate （TL）-pulsed dendritic cells （DCs） and cytokine-induced killer （CIK） cells in patients with localized or locally advanced RCC.展开更多
Solid tumour cells show a resistance to immunological effector cells in vitro. The resistance may be one reason why these tumours withstand immunotherapeutic approaches in humans. Dendritic cells （DC） play an impor...Solid tumour cells show a resistance to immunological effector cells in vitro. The resistance may be one reason why these tumours withstand immunotherapeutic approaches in humans. Dendritic cells （DC） play an important role in the immune response to tumour associated antigens in humans. DC in the periphery capture and process antigens, express lymphocyte costimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune response.展开更多
Objective： To investigate the proliferation capabilities, immunophenotype changes, level of secreted cytokines and activities against lymphoma cells under the condition that cytokine-induced killer （CIK） cells co-c...Objective： To investigate the proliferation capabilities, immunophenotype changes, level of secreted cytokines and activities against lymphoma cells under the condition that cytokine-induced killer （CIK） cells co-cultured with dendritic cells （DC） in vitro. Methods： DC and CIK cells were induced from peripheral blood mononuclear cells of healthy volunteers. They were co-cultured meanwhile CIK cells were cultured alone as controls. Increased number of cells were counted by tapan-blue staining, killing activities were detected by MTT assay, immunophenotype changes were analyzed by flow cytometry, the IL-12 and INF-y levels of the cultured supernatants were detected by ELISA kits. Results： The proliferation capabilities of DC-CIK cells were significantly higher than that of CIK cells （P 〈 0.05）. Under the same condition, the ratio of double positive cells such as CD3^＋ CD8^＋, CD3^＋ CD56^＋ in CIK cells was significantly enhanced by co-cultured with DC cells （P 〈 0.05）. The level of IL-12 and INF-y secreted in supernatants was increased noticeably by co-cultured DC-CIK cells on day 3 compared to CIK cells which were cultured alone （P 〈 0.01 and P 〈 0.05）. Within the effector-target ratio range between 5：1 to 40：1, the activities against lymphoma cells of DC-CIK cells were much higher than that of CIK cells （P 〈 0.05）, and this effect was showed a positive correlation with the effector-target ratio. Conclusion： The proliferation capabilities, the level of secreted cytokines and the activities against lymphoma cells of DC-CIK cells were significantly higher than those of CIK cells. The research might provides theoretical and experimental basis for clinical immunotherapy of DC-CIK cells.展开更多
AIM: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intraand extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer. ME...AIM: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intraand extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer. METHODS: We divided 45 patients into cryo-immunotherapy (21 patients), cryotherapy (n = 12), immunotherapy (n = 5) and untreated (n = 7) groups. Overall survival (OS) after diagnosis of metastatic hepatocellular cancer was assessed after an 8-year follow-up. RESULTS: Median OS was higher following cryo-immu-notherapy (32 mo) or cryotherapy (17.5 mo; P < 0.05) than in the untreated group (3 mo) and was higher in the cryo-immunotherapy group than in the cryotherapy group (P < 0.05). In the cryo-immunotherapy group, median OS was higher after multiple treatments (36.5 mo) than after a single treatment (21 mo; P < 0.05). CONCLUSION: Cryotherapy and, especially, cryoimmunotherapy significantly increased OS in metastatic hepatocellular cancer patients. Multiple cryo-immunotherapy was associated with a better prognosis than single cryo-immunotherapy.展开更多
Objective： The aim of this study was to observe the therapeutic effect of cytokine induced killer （CIK） cells in combination with dendritic cells （DCs） on advanced solid carcinoma patients. Methods： Isolated per...Objective： The aim of this study was to observe the therapeutic effect of cytokine induced killer （CIK） cells in combination with dendritic cells （DCs） on advanced solid carcinoma patients. Methods： Isolated peripheral blood mononuclear cells （PBMCs） from 110 advanced solid tumor patients. Added granulocyte-macrophage colony-stimulating factor （GM-CSF）, tumor necrosis factor-a （TNF-a） and interleukin-4 （IL-4） to adherent cells to induce DCs, and sensitized DCs with antigens of autologous tumor cells or extrinsic tumor cell lines. Cultured suspending cells with interferon-y （IFN-y）, interleukin-2 （IL-2） and CD3 monoclonal antibody （CD3 McAb） to prepare CIK cells, then co-cultured with DCs. After analyzing the phenotype and checking tumor markers and immune function, the autologous CIK cells and DCs were transfused into the cancer patients. Results： Forty-two patients with measurable nidus, 2 achieved complete remission （CR）, 9 partial remission （PR） and 15 stable disease （SD）, while 37 patients with immeasurable nidus, 25 had efficient response. The tumor markers and immune function both improved significantly compared with those before treatment. Conclusion： DCs and CIK cells combinational treatment is safe and effective on advanced solid carcinoma and provide a new and efficacious immunity therapeutic methods for the cancer patients.展开更多
Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor imm...Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.展开更多
文摘BACKGROUND Hepatocellular carcinoma(HCC) has been revealed as the second most common cause of cancer-related deaths worldwide. The introduction of cell-based immunotherapy, including dendritic cells(DCs) and cytokine-induced killer cells(CIKs), has brought HCC patients an effective benefit. However, the efficacy and necessity of cellular immunotherapy after different interventional therapy remains to be further explored.AIM To investigate the efficacy of cellular immunotherapy, involving DCs and CIKs,combined with different conventional treatments of HCC.METHODS We performed a literature search on PubMed and Web of Science up to February15, 2019. Long-term efficacy(overall survival and recurrence) and short-term adverse effects were investigated to assess the effectiveness of immunotherapy with DCs and/or CIKs. Review Manager 5.3 was used to perform the analysis.RESULTS A total of 22 studies involving 3756 patients selected by eligibility inclusion criteria were forwarded for meta-analysis. Combined with the conventional clinical treatment, immunotherapy with DCs and/or CIKs was demonstrated to significantly improve overall survival at 6 mo [risk ratio(RR) = 1.07;95%confidence interval(CI): 1.01-1.13, P = 0.02], 1 year(RR = 1.12;95%CI: 1.07-1.17, P< 0.00001), 3 years(RR = 1.23;95%CI: 1.15-1.31, P < 0.00001) and 5 years(RR =1.26;95%CI: 1.15-1.37, P < 0.00001). Recurrence rate was significantly reduced by cellular immunotherapy at 6 mo(RR = 0.50;95%CI: 0.36-0.69, P < 0.0001) and 1 year(RR = 0.82;95%CI: 0.75-0.89, P < 0.00001). Adverse effect assessment addressed that immunotherapy with DCs and/or CIKs was accepted as a safe,feasible treatment.CONCLUSION Combination immunotherapy with DCs, CIKs and DC/CIK with various routine treatments for HCC was evidently suggested to improve patients’ prognosis by increasing overall survival and reducing cancer recurrence.
基金Supported by Hong Kong Wang Kuan Cheng GrantInner Mongolia Stem Cell Grant, No. kjk10jhg
文摘AIM： To evaluate the safety and clinical efficacy of a new immunotherapy using both α-Gal epitope-pulsed dendritic cells （DCs） and cytokine-induced killer cells. METHODS： Freshly collected hepatocellular carcinoma （HCC） tumor tissues were incubated with a mixture of neuraminidase and recombinant αl,3-galactosyltrans- ferase （αI,3GT） to synthesize α-Gal epitopes on car- bohydrate chains of the glycoproteins of tumor mem- branes. The subsequent incubation of the processed membranes in the presence of human natural anti-Gal IgG resulted in the effective phagocytosis to the tumor membrane by DCs. Eighteen patients aged 38-78 years with stage 111 primary HCC were randomly chosen for the study; 9 patients served as controls, and 9 patients were enrolled in the study group.RESULTS： The evaluation demonstrated that the pro- cedure was safe; no serious side effects or autoimmune diseases were observed. The therapy significantly pro- longed the survival of treated patients as compared with the controls （17.1 ± 2.01 mo vs 10.1 ±4.5 mo, P = 0.00121）. After treatment, all patients in the study group had positive delayed hypersensitivity and robust systemic cytotoxicity in response to tumor lysate as measured by interferon-y-expression in peripheral blood mononuclear cells using enzyme-linked immunosorbent spot assay. They also displayed increased numbers of CD8-, CD45RO- and CD56-positive cells in the peripheral blood and decreased α-fetoprotein level in the se- rum. CONCLUSION： This new tumor-specific immunotherapy is safe, effective and has a great potential for the treat- ment of tumors.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 30772178）, Medical Research Fund of Science and Technology of Guangdong （No. B2007062）, Research Fund for the Doctoral Program of Higher Education of China （No. 20060558032）, Natural Science Foundation of Guangdong Province （No. 7117362） and the Program of 5010 of Sun Yat-sen Universitty （No. 2007028）. Conflicts of interest： none.
文摘Background It remains a challenge to inhibit the local recurrence or distant metastasis of localized or locally advanced renal cell carcinoma （RCC） after surgical resection. We investigated the feasibility, safety and efficacy of immunotherapy using autologous tumor lysate （TL）-pulsed dendritic cells （DCs） and cytokine-induced killer （CIK） cells in patients with localized or locally advanced RCC.
文摘Solid tumour cells show a resistance to immunological effector cells in vitro. The resistance may be one reason why these tumours withstand immunotherapeutic approaches in humans. Dendritic cells （DC） play an important role in the immune response to tumour associated antigens in humans. DC in the periphery capture and process antigens, express lymphocyte costimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune response.
基金the Shanxi Social Development Key Fundation (No. 2007k0902)
文摘Objective： To investigate the proliferation capabilities, immunophenotype changes, level of secreted cytokines and activities against lymphoma cells under the condition that cytokine-induced killer （CIK） cells co-cultured with dendritic cells （DC） in vitro. Methods： DC and CIK cells were induced from peripheral blood mononuclear cells of healthy volunteers. They were co-cultured meanwhile CIK cells were cultured alone as controls. Increased number of cells were counted by tapan-blue staining, killing activities were detected by MTT assay, immunophenotype changes were analyzed by flow cytometry, the IL-12 and INF-y levels of the cultured supernatants were detected by ELISA kits. Results： The proliferation capabilities of DC-CIK cells were significantly higher than that of CIK cells （P 〈 0.05）. Under the same condition, the ratio of double positive cells such as CD3^＋ CD8^＋, CD3^＋ CD56^＋ in CIK cells was significantly enhanced by co-cultured with DC cells （P 〈 0.05）. The level of IL-12 and INF-y secreted in supernatants was increased noticeably by co-cultured DC-CIK cells on day 3 compared to CIK cells which were cultured alone （P 〈 0.01 and P 〈 0.05）. Within the effector-target ratio range between 5：1 to 40：1, the activities against lymphoma cells of DC-CIK cells were much higher than that of CIK cells （P 〈 0.05）, and this effect was showed a positive correlation with the effector-target ratio. Conclusion： The proliferation capabilities, the level of secreted cytokines and the activities against lymphoma cells of DC-CIK cells were significantly higher than those of CIK cells. The research might provides theoretical and experimental basis for clinical immunotherapy of DC-CIK cells.
文摘AIM: To retrospectively assess the effect of comprehensive cryosurgery (ablation of intraand extra-hepatic tumors) plus dendritic cell-cytokine-induced killer cell immunotherapy in metastatic hepatocellular cancer. METHODS: We divided 45 patients into cryo-immunotherapy (21 patients), cryotherapy (n = 12), immunotherapy (n = 5) and untreated (n = 7) groups. Overall survival (OS) after diagnosis of metastatic hepatocellular cancer was assessed after an 8-year follow-up. RESULTS: Median OS was higher following cryo-immu-notherapy (32 mo) or cryotherapy (17.5 mo; P < 0.05) than in the untreated group (3 mo) and was higher in the cryo-immunotherapy group than in the cryotherapy group (P < 0.05). In the cryo-immunotherapy group, median OS was higher after multiple treatments (36.5 mo) than after a single treatment (21 mo; P < 0.05). CONCLUSION: Cryotherapy and, especially, cryoimmunotherapy significantly increased OS in metastatic hepatocellular cancer patients. Multiple cryo-immunotherapy was associated with a better prognosis than single cryo-immunotherapy.
基金Supported by a grant from the Foundation of Chongqing Municipal Health Bureau (No. 2010-2-301)
文摘Objective： The aim of this study was to observe the therapeutic effect of cytokine induced killer （CIK） cells in combination with dendritic cells （DCs） on advanced solid carcinoma patients. Methods： Isolated peripheral blood mononuclear cells （PBMCs） from 110 advanced solid tumor patients. Added granulocyte-macrophage colony-stimulating factor （GM-CSF）, tumor necrosis factor-a （TNF-a） and interleukin-4 （IL-4） to adherent cells to induce DCs, and sensitized DCs with antigens of autologous tumor cells or extrinsic tumor cell lines. Cultured suspending cells with interferon-y （IFN-y）, interleukin-2 （IL-2） and CD3 monoclonal antibody （CD3 McAb） to prepare CIK cells, then co-cultured with DCs. After analyzing the phenotype and checking tumor markers and immune function, the autologous CIK cells and DCs were transfused into the cancer patients. Results： Forty-two patients with measurable nidus, 2 achieved complete remission （CR）, 9 partial remission （PR） and 15 stable disease （SD）, while 37 patients with immeasurable nidus, 25 had efficient response. The tumor markers and immune function both improved significantly compared with those before treatment. Conclusion： DCs and CIK cells combinational treatment is safe and effective on advanced solid carcinoma and provide a new and efficacious immunity therapeutic methods for the cancer patients.
基金Supported by(in part)Research Programs on the Innovative Development and Application for New Drugs for Hepatitis B(No.17fk0310116h0001) from the Japan Agency for Medical Research and Development(AMED)Extramural Collaborative Research Grant of Cancer Research Institute,Kanazawa University
文摘Tumor immunity proceeds through multiple processes, which consist of antigen presentation by antigen presenting cells(APCs) to educate effector cells and destruction by the effector cytotoxic cells. However, tumor immunity is frequently repressed at tumor sites. Malignantly transformed cells rarely survive the attack by the immune system, but cells that do survive change their phenotypes to reduce their immunogenicity. The resultant cells evade the attack by the immune system and form clinically discernible tumors. Tumor microenvironments simultaneously contain a wide variety of immune suppressive molecules and cells to dampen tumor immunity. Moreover, the liver microenvironment exhibits immune tolerance to reduce aberrant immune responses to massively-exposed antigens via the portal vein, and immune dysfunction is frequently associated with liver cirrhosis, which is widespread in hepatocellular carcinoma(HCC) patients. Immune therapy aims to reduce tumor burden, but it is also expected to prevent non-cancerous liver lesions from progressing to HCC, because HCC develops or recurs from noncancerous liver lesions with chronic inflammatory states and/or cirrhosis and these lesions cannot be cured and/or eradicated by local and/or systemic therapies. Nevertheless, cancer immune therapy should augment specific tumor immunity by using two distinct measures: enhancing the effector cell functions such as antigen presentation capacity of APCs and tumor cell killing capacity of cytotoxic cells, and reactivating the immune system in immune-suppressive tumor microenvironments. Here, we will summarize the current status and discuss the future perspective on immune therapy for HCC.
