1.Recent advances in antibody-drug conjugates for metastatic castration-resistant prostate cancer.
Jiacheng XU ; Yutao MA ; Pengcheng HU ; Jiatao YAO ; Haichao CHEN ; Qi MA
Journal of Zhejiang University. Medical sciences 2025;54(5):685-693
Patients with metastatic castration-resistant prostate cancer (mCRPC) face poor prognoses due to tumor heterogeneity and drug resistance. Antibody-drug conjugates (ADCs) have been under development for over two decades for mCRPC treatment. Several clinical trials have demonstrated promising antitumor activity and acceptable safety profiles for ADCs in this setting. Among prostate-specific membrane antigen (PSMA)-targeted ADCs, ARX517 demonstrates superior safety and more significant prostate-specific antigen (PSA) reductions compared to earlier agents such as MLN2704, PSMA-ADC, and MEDI3726. ADCs targeting B7-H3, such as MGC018 and DB-1311, have also shown antitumor activity. ADCs targeting other antigens, including six-transmembrane epithelial antigen of the prostate (STEAP)1 (DSTP3086S), trophoblast cell surface antigen (TROP)2 (sacituzumab govitecan), and solute carrier (SLC) 44A4 (ASG-5ME), have shown preliminary antitumor activity in early trials but face challenges with insufficient efficacy or toxicity. Tisotumab vedotin (targeting tissue factor) has shown no significant therapeutic response in mCRPC. Meanwhile, disitamab vedotin (HER2-targeted), ABBV-969 and DXC008 (both dual PSMA/STEAP1-targeted) are currently under evaluation. Notably, an international multicenter phase Ⅲ clinical trial (NCT06925737) for mCRPC has been initiated in May 2025 for evaluating B7-H3-targeted ADC ifinatamab deruxtecan. This review summarizes recent advances in ADCs targeting key antigens in mCRPC (including PSMA, B7-H3, STEAP1, TROP2, SLC44A4, and others) and explores combination strategies, offering insights to inform the clinical management of mCRPC.
Humans
;
Prostatic Neoplasms, Castration-Resistant/pathology*
;
Male
;
Immunoconjugates/therapeutic use*
;
Glutamate Carboxypeptidase II/immunology*
;
Antibodies, Monoclonal, Humanized/therapeutic use*
;
B7 Antigens/immunology*
;
Neoplasm Metastasis
;
Prostate-Specific Antigen
;
Antigens, Neoplasm/immunology*
;
Antigens, Surface
;
Camptothecin/analogs & derivatives*
;
Oxidoreductases
2.Influence of blocking B7/CD28 and CD40/CD154 co-stimulatory signals on immune function of sensitized mice.
Qi-Xiang YE ; Lu-Hong XU ; Wei XU ; Jian-Pei FANG
Journal of Experimental Hematology 2014;22(3):801-806
This study was aimed to explore the effects of blocking B7/CD28 and CD40/CD154 co-stimulatory signals on immune function of sensitized mice', and provide the evidences of acquired immune tolerance for allogeneic bone marrow transplantation. The mice sensitized on 7 day before transplant were divided into 4 groups: (1)CTLA4Ig+ anti-CD154 isotype control IgG; (2)anti-CD154 +CTLA4Ig isotype control IgG; (3)CTLA4Ig and anti-CD154; (4)isotype control IgG of CTLA4Ig and anti-CD154. CTLA4Ig and anti-CD154 used in normal BALB/c mice as isotype control IgG. Each mouse in all groups received CTLA4Ig and anti-CD154 (or corresponding isotype control IgG) 500 µg respectively, and was injected via tail vein on 7 day before transplant. There were 5 mice in each group. The mice were sacrificed on day 0, then the number of CD19(+)CD69(+)B cells, CD44(high)/CD62L(high) and CD44(high)/CD62L(low)/- T cells were measured by flow cytometry. Changes of cytokines and sensitized antibody were tested by ELISA or flow cytometry. The results showed that the numbers of CD19(+)CD69(+)B cells were significantly increased in comparison with the normal group (P < 0.01) , whereas the numbers of cells were significantly decreased when blocking B7/CD28 or /and CD40/CD154 co-stimulatory signals (P < 0.01) . Blocking these 2 signals together displayed a synergistic effect (P < 0.01) . The central memory and effector T cells were defined as CD44(high)/CD62L(high) and CD44(high)/CD62L(low)/- respectively, those increased significantly after sensitized in comparison with those in normal group, whereas their numbers decreased when blocking B7/CD28 or/and CD40/CD154 co-stimulatory signals. Blocking these two signals together, displayed a synergistic effect (P < 0.01). Cytokines, IgG and IgM in all groups were not significantly different. Sensitizing antibody test showed that the fluorescence intensity of sensitized group significantly increased as compared with normal group, whereas fluorescence intensity of CTLA4Ig or/and anti-CD154 treated groups significantly decreased as compared with sensitized group (P < 0.01) . It is concluded that blocking the B7/CD28 or/and CD40/CD154 co-stimulatory signal can inhibit the cellular and humoral immune function, whereas blocking these two signals together displays a synergistic effect.
Animals
;
B7-1 Antigen
;
metabolism
;
Bone Marrow Transplantation
;
CD28 Antigens
;
metabolism
;
CD40 Antigens
;
metabolism
;
CD40 Ligand
;
metabolism
;
Immune Tolerance
;
immunology
;
Male
;
Mice
;
Mice, Inbred BALB C
;
Mice, Inbred C57BL
;
Signal Transduction
;
Transplantation, Homologous
3.Expression of PD-1/PD-L1 in peripheral blood mononuclear cells in lung cancer patients and its biological significance.
Ping XU ; Hui CHEN ; Yong-jing CHEN ; Yan-bin CHEN ; Guo-hao GU ; Mei-ying WU ; Min-juan WU ; Xue-feng WANG ; Xue-guang ZHANG
Chinese Journal of Oncology 2013;35(12):910-913
OBJECTIVETo analyze the expression of co-stimulatory molecules PD-1/PD-L1 in peripheral blood mononuclear cells in lung cancer patients, and to explore its biological significance.
METHODSOne hundred and thirty-three lung cancer patients, 25 lung infection patients and 23 healthy donors were enrolled in this study. 100 µl of whole blood from these subjects were collected. Multi-color immunofluorescence staining and flow cytometry were used to detect PD-1/PD-L1 expression. The results were statistically analyzed.
RESULTSThe expression level of CD3⁺CD8⁺ T cells in the lung cancer patients was (38.83 ± 1.74)%, significantly lower than that in the control group [(43.25 ± 3.35)%, P < 0.05]. CD8⁺CD28⁺ T cell subset in the peripheral blood of lung cancer patients was (17.73 ± 1.21)% significantly lower than that of the healthy donors [(27.96 ± 2.72)%, P < 0.01]. The CD8⁺CD28⁻ T cell subset was (21.19 ± 1.92)% in the lung cancer patients, significantly higher than that of the healthy control group [(15.18 ± 2.93)%, P < 0.05]. The expression level of PD-1 on the surface of CD8⁺CD28⁺ T cells was (10.67 ± 1.12)% in the group of lung cancer patients, significantly higher than that of the control group [(5.32 ± 1.58)%, P < 0.01]. It was also found that the expression of PD-1 on CD8⁺CD28⁻ T cells was up-regulated in the group of lung cancer patients (7.46 ± 1.25)%, significantly higher than that of the healthy control group [(2.68+1.07)%, P < 0.01]. The expression level of PD-L1 on CD68⁺ cells in the lung cancer patients was (16.03 ± 2.06)%, significantly higher than that of the healthy control group [(9.32 ± 2.00)%, P < 0.05].
CONCLUSIONUp-regulation of PD-1/PD-L1 on peripheral blood cells in lung cancer patients negatively regulates the lymphocytes, inhibits the immune response for killing tumor cells, and promotes tumor development and immune escape.
Adenocarcinoma ; blood ; pathology ; B7-H1 Antigen ; metabolism ; CD28 Antigens ; metabolism ; CD3 Complex ; metabolism ; CD8 Antigens ; metabolism ; Carcinoma, Large Cell ; blood ; pathology ; Carcinoma, Squamous Cell ; blood ; pathology ; Case-Control Studies ; Female ; Humans ; Lung Neoplasms ; blood ; pathology ; Male ; Middle Aged ; Programmed Cell Death 1 Receptor ; metabolism ; Small Cell Lung Carcinoma ; blood ; pathology ; T-Lymphocytes ; immunology ; metabolism ; Up-Regulation
4.Effects of Bushen Jiedu Recipe and Jianpi Jiedu Recipe containing plasma on dendritic cells of chronic hepatitis B virus infection patients under different immune states.
Song OU ; Ke-Wei SUN ; Jian-Ping PENG ; Shuang-Lin QI ; Jie WEN ; Li HU
Chinese Journal of Integrated Traditional and Western Medicine 2013;33(2):208-213
OBJECTIVETo compare the effects of Bushen Jiedu Recipe (BJR) and Jianpi Jiedu Recipe (JJR) containing plasma on dendritic cells (DCs) of chronic hepatitis B virus (HBV) infection patients under different immune states.
METHODSRecruited were 36 chronic HBV infection outpatients from First Affiliated Hospital of Hunan University of Traditional Chinese Medicine from April 2010 to January 2011. They were assigned to the immune tolerance group (18 cases) and the immune clearance group (18 cases).Another 10 healthy subjects were recruited as the healthy control group. Their anticoagulated peripheral venous blood was respectively collected. The peripheral blood mononuclear cells (PBMCs) were isolated and further extracted for incubating DCs. The DCs were intervened by BJR and JJR containing plasma. The morphology of DCs was identified. The expressions of CD1alpha, CD80, CD86, and HLA-DR were detected. The level of interferon-alpha (IFN-alpha) in the supernatant was observed by ELISA.
RESULTSThe CD80 expression level was lower in the immune clear group than in the healthy control group before intervention (P < 0.05). The expression levels of CD80, CD86, and HLA-DR were lower in the immune tolerance group than in the healthy control group before intervention (P < 0.05).The IFN-alpha expression level was lower in the immune tolerance group and the immune clearance group than in the healthy control group before intervention (P < 0.05). The expression levels of CD80, HLA-DR, and IFN-alpha were lower in the immune tolerance group than in the immune clearance group before intervention (P < 0.05). Compared with the same group before intervention, the CD80 expression significantly increased in each treatment group (P < 0.05). After intervention the expression levels of CD80 and HLA-DR were higher in the immune tolerance group than in the immune clearance group in the same time phase, and the CD86 expression level was higher in the BJR group than in the immune clearance group in the same time phase, showing statistical difference (P < 0.05).
CONCLUSIONSThe middle dose BJR and the small dose JJR both could promote the recovery of DCs in chronic HBV infection patients. Besides, BJR showed more prominent effects on the function of DCs in chronic HBV infection patients in the immune tolerance stage.
Adult ; B7-1 Antigen ; metabolism ; B7-2 Antigen ; metabolism ; Case-Control Studies ; Dendritic Cells ; drug effects ; immunology ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; HLA-DR Antigens ; metabolism ; Hepatitis B, Chronic ; blood ; drug therapy ; immunology ; Humans ; Immune Tolerance ; drug effects ; Interferon-alpha ; metabolism ; Male ; Phytotherapy ; Plasma ; Young Adult
5.Clinical significance of costimulatory molecule B7-H3 expression on CD3(+) T cells in colorectal carcinoma.
Yong MAO ; Jing SUN ; Wei-peng WANG ; Xue-guang ZHANG ; Dong HUA
Chinese Medical Journal 2013;126(16):3035-3038
BACKGROUNDB7-H3 has been widely studied in the context of tumor progression in recent years, and behaves as a tumor cell marker in a variety of tumors including colorectal carcinoma. The mechanism of B7-H3 in tumor progression is complicated and not clear yet. Studies have revealed that B7 family molecules are expressed on infiltrated lymphocytes as well as tumor cells in tumor microenvironment, which indicates that different expression pattern may lead to different clinical outcomes.
METHODSThe expression of B7-H3 was detected in tissues of 98 colorectal carcinoma patients by using immunohistochemistry. Then the expression of B7-H3 on CD3(+) T lymphocytes isolated from fresh cancer tissues of 12 colorectal carcinoma patients was analyzed by flow cytometry assay. The relationship between the expression of B7-H3 on CD3(+) T lymphocytes and patients' clinical pathological parameters was demonstrated with statistical analysis.
RESULTSPatients with more CD3(+) T cell infiltration survived much longer than patients with less CD3(+) T cell infiltration (P < 0.05); B7-H3 was highly expressed by infiltrating CD3(+) T lymphocytes in colorectal carcinoma tissues. The expression of B7-H3 was found to be significantly related with lymph node metastasis status (P < 0.05), but not with the patient's gender, age, tumor size, differentiation degree, depth of tumor invasion, Dukes' stage, distant metastasis and whether or not mucinous adenocarcinoma was present (P > 0.05). Moreover, the survival time of patients with low expression of B7-H3 was obviously longer than those of high B7-H3 expression patients, but the seven-year survival rate showed no difference between the high and low B7-H3 expression patients (P > 0.05).
CONCLUSIONThe negative costimulatory molecule B7-H3 on infiltrating CD3(+) T lymphocytes in colorectal carcinoma bears importance in the clinical pathological progress and prognosis of colorectal carcinoma.
Adult ; Aged ; B7 Antigens ; analysis ; CD3 Complex ; analysis ; Colorectal Neoplasms ; immunology ; mortality ; pathology ; Female ; Flow Cytometry ; Humans ; Immunohistochemistry ; Lymphocytes, Tumor-Infiltrating ; immunology ; Male ; Middle Aged ; Survival Rate ; T-Lymphocytes ; immunology
6.Study on the functions of peripheral dendritic cells in chronic hepatitis B virus infection patients of Gan-depression Pi-deficiency syndrome and Gan-Dan damp-heat syndrome under different immune states.
Fang HE ; Ke-wei SUN ; Jian-ping PENG
Chinese Journal of Integrated Traditional and Western Medicine 2011;31(11):1491-1495
OBJECTIVETo observe the functions of peripheral dendritic cells (DCs) in chronic hepatitis B virus (HBV) infection patients of Gan-depression Pi-deficiency syndrome (GPS) and Gan-Dan damp-heat syndrome (GDS) under different immune states, thus to study the features of the immune expressions of the two syndromes in chronic HBV infection, providing objective evidence for Chinese medicine syndrome typing.
METHODSThe 40 chronic HBV patients were randomly assigned to two groups according to the immune state. Of them, there were 20 chronic HBV patients (under the condition of immune clearance; consisting of 10 patients of GPS and 10 of GDS) and 20 chronic HBV carriers (under the condition of immune tolerance; consisting of 10 patients of GPS and 10 of GDS). Besides, 10 healthy graduate volunteers of Hunan University of Traditional Chinese Medicine were recruited as the healthy control group. Their peripheral blood mononuclear cells (PBMCs) were cultured in vitro. The exterior morphological features and ultrastructure were observed by inverted microscope and electron microscope. The expressions of HLA-DR, CD80, CD86, and CDIa of the DCs surface were detected. The secretory levels of IL-12 in the supernate of DCs were detected by ELISA reagent kit. The proliferation capacities of allogeneic mixed lymphocyte were detected using MTT. The function features of DCs in the chronic HBV patients of two syndrome types under different immune states were compared, thus analyzing the difference of each index between the two syndrome types.
RESULTSCompared with the healthy control group, the expression rates of CD86, CD80, and HLA-DR decreased in the HBV carriers group (of the two syndrome types), showing statistical difference (P < 0.05). The expression rate of CD80 decreased in the HBV group (of the two syndrome types), showing statistical difference (P < 0.05). The expression rates of CD86 and HLA-DR were lower in the GPS group than in the GDS group. The expression rate of CD80 was lower in the GPS group than in the GDS group, showing statistical difference (P < 0.05). The proliferation capacities of IL-12 and T lymphocytes were lower in the HBV patients group than in the healthy control group (P < 0.05). The proliferation capacities of IL-12 and T lymphocytes were lower in the GPS group than in the GDS group, showing statistical difference (P < 0.05).
CONCLUSIONSThe functions of peripheral DCs in chronic HBV infection of patients of the GPS and the GDS under different immune states were different. The phenotype and function tests of DCs provided objective evidence for Chinese syndrome typing of chronic hepatitis B, thus reflecting the features of immune expressions of the two syndrome types and the immunology connotation.
Adult ; B7-1 Antigen ; metabolism ; B7-2 Antigen ; metabolism ; Case-Control Studies ; Cells, Cultured ; Dendritic Cells ; immunology ; Female ; HLA-DR Antigens ; metabolism ; Hepatitis B, Chronic ; blood ; diagnosis ; immunology ; Humans ; Interleukin-12 ; immunology ; Male ; Medicine, Chinese Traditional ; T-Lymphocytes ; immunology ; Young Adult
7.Anti-cD20scFv/CD80/CD28/zeta specific T lymphocytes eradicate primary chronic lymphocytic leukemia cells in vitro.
Hong-Lan QIAN ; Kang YU ; Zhi-Jian SHEN ; Bin LIANG ; Sheng LUO ; Chong-Yun XING ; Yong-Xian HU
Chinese Journal of Applied Physiology 2010;26(4):436-439
OBJECTIVETo construct anti-CD20scFv/CD80/CD28/zeta recombinant gene modified T cells, test its effectiveness of eradicating CD20 positive primary chronic lymphocytic leukemia (CLL) cells and provide a promising tool for tumor adoptive immunotherapy.
METHODSThe recombinant vectors were transduced into PA 317 cells and high titer retroviruses were obtained to infect human peripheral blood T lymphocytes. Resistant T cells were obtained by G418 selection for one week. Then transduced T lymphocytes and primary CLL cells were co-cultured. The status of primary chronic lymphocytic leukemia cells were observed by microscope. The level of IL-2 and IFN-gamma in the culture medium were measured.
RESULTSPrimary T cells expressing anti-CD20scFv/IgGFc/CD80/CD28/zeta could be constructed successfully. These T cells were able to lyse CD20+ targets and secrete high levels of IL-2 (1301.00 pg/ml) and IFN-gamma (602.18 pg/ml) in vitro.
CONCLUSION(1) Recombinant gene modified T cells can be constructed successfully. (2) Recombinant gene modified T cells can specially kill CD20 positive primary CLL cells in vitro.
Antigens, CD20 ; genetics ; B7-1 Antigen ; genetics ; CD28 Antigens ; genetics ; Genetic Vectors ; Humans ; Immunotherapy, Adoptive ; Interferon-gamma ; secretion ; Interleukin-2 ; secretion ; Leukemia, Lymphocytic, Chronic, B-Cell ; pathology ; Retroviridae ; genetics ; T-Lymphocytes ; immunology ; secretion ; Transfection ; Tumor Cells, Cultured
8.Effect of sirolimus on capacity of splenic dendritic cells from traumatized mice in inducing T cell responses ex vivo.
Yong-jiu TU ; Xia FAN ; Xue YANG ; Xi WANG ; Qiang WEI ; Hua-ping LIANG
Chinese Journal of Burns 2010;26(2):90-94
OBJECTIVETo study the ex vivo effect of sirolimus on capacity of splenic dendritic cells (DC) from traumatized mice in inducing T cell responses.
METHODSTwenty-four BALB/c mice were divided into control group and trauma group according to the random number table, with 12 mice in each group. Mice in trauma group were bled followed by closed femur fracture after anaesthesia, while mice in control group were only anaesthetized without injury. Twenty-four hours later DC were isolated from spleens and divided into 4 subgroups: sirolimus devoid control (trauma) groups [consisted of cells from control (trauma) groups, without sirolimus treatment] and sirolimus treated control (trauma) groups [consisted of cells from control (trauma) groups, treated with 10 microg/L sirolimus for 6 hours]. Then their autophagic activity, DC-induced mixed lymphocyte reaction (MLR) were measured and recorded as fluorescence intensity (FI) value and absorbance value respectively. The expression of major histocompatibility complex class (MHC) II and costimulatory molecules CD40, CD80, and CD86 on DC surface were measured with flow cytometry. IL-12p40, IL-12p70 and IL-10 levels in lipopolysaccharide-stimulated DC supernatants were determined by ELISA. Data were processed with one-way analysis of variance.
RESULTS(1) Compared with those of sirolimus devoid control group (FI value = 22 +/- 6), DC autophagic activity (FI value = 13 +/- 2) and DC-induced MLR in mice from sirolimus devoid trauma group were significantly weakened (F = 212.836, P < 0.05). Compared with those of sirolimus devoid control (trauma) groups, DC autophagic activity in mice from sirolimus treated control (trauma) groups (FI = 45 +/- 8, 44 +/- 8 respectively) were significantly strengthened (F = 212.836, P < 0.05 or P < 0.01). MLR in mice from sirolimus treated trauma group was stronger than that from sirolimus devoid trauma group (with F value respectively 101.426, 86.533, P values all below 0.05). (2) Compared with those of sirolimus devoid control group [MHC II (85 +/- 6)%, CD40 (8 +/- 1)%], the expressions of MHCII [(60 +/- 9)%] and CD40 [(4 +/- 1)%] on DC surface from sirolimus devoid trauma group were significantly reduced (with F value respectively 37.918, 40.426, P values all below 0.05). The expression of MHCII from sirolimus treated trauma group [(78 +/- 7)%] was higher than that from sirolimus devoid trauma group (F = 37.918, P < 0.05). (3) IL-12p40, IL-12p70 secretion by DC from sirolimus devoid trauma group [(120 +/- 13), (10 +/- 3) pg/mL] were significantly reduced as compared with those from sirolimus devoid control group [(200 +/- 25), (20 +/- 6) pg/mL, with F value respectively 218.646, 310.253, P values all below 0.05]. Compared with those from sirolimus devoid control (trauma) groups, IL-12p40 [(560 +/- 34), (540 +/- 29) pg/mL], IL-12p70 [(55 +/- 8), (60 +/- 11) pg/mL] secretion by DC from sirolimus treated control (trauma) groups were obviously enhanced (with F value respectively 218.646, 310.253, P values all below 0.01), while IL-10 secretion levels were significantly decreased (F = 246.108, P < 0.01).
CONCLUSIONSSirolimus can partially ameliorate DC functions ex vivo in traumatized mice, and further enhance the capacity of DC in inducing T cell responses.
Animals ; B7-1 Antigen ; metabolism ; B7-2 Antigen ; metabolism ; CD40 Antigens ; metabolism ; Dendritic Cells ; drug effects ; immunology ; metabolism ; Histocompatibility Antigens Class II ; immunology ; Interleukin-12 Subunit p40 ; metabolism ; Lymphocyte Culture Test, Mixed ; Male ; Mice ; Mice, Inbred BALB C ; Sirolimus ; pharmacology ; Spleen ; cytology ; immunology ; T-Lymphocytes ; immunology ; Wounds and Injuries ; immunology
9.Programmed death-1 (PD-1) and PD-L1 expression during antiviral treatment of chronic hepatitis B.
Dong-ying XIE ; Bing-liang LIN ; Feng-juan CHEN ; Hong DENG ; Yu-tian CHONG ; Xiao-hong ZHANG ; Zhi-liang GAO
Chinese Journal of Hepatology 2010;18(9):646-650
OBJECTIVETo study PD-1 and PD-L1 expressions during 24 weeks telbivudine antiviral treatment in patients with chronic hepatitis B (CHB) and to explore the relationship between PD-1 expression and HBeAg/HBeAb seroconversion.
METHODSTen CHB cases with HLA-A2 and HBeAg positive were treated with telbivudine 600 mg/d orally for 24 weeks. Fresh blood samples were collected at week 0, 12 and 24 after treatment. HBV-specific CD8+ T cells were expanded in vitro. Cell culture medium were collected for interferon gamma (IFNgamma) detection. Flow cytometry was used to detect the HLA-A type, PD-1, PD-L1 and HBV specific CD8+ T cells. The expressions of PD-1 and PD-L1, the counts of HBV-specific CD8+ T cells in circulating CD8+ lymphocytes, and IFNgamma concentration in culture medium were evaluated during antiviral treatment.
RESULTSAt week 0, 12 and 24 after telbivudine treatment, 7 of 10 patients were HBV DNA undetectable, 2 were HBeAg seroconversion and 2 were HBeAg lose but anti-HBe negative. The frequency of PD-1-positive PBMCs were 52.1%+/-17.0%, 39.1%+/-18.2% and 23.4%+/-16.3% (week 24 vs week 0, P < 0.01) respectively; PD-L1 positive PBMCs were 45.6%+/-15.4%, 34.6%+/-16.2% and 20.9%+/-9.5% respectively(week 24 vs week 0, P < 0.01; week 24 vs week 12, P < 0.05). The frequency of PD-1-positive CD8+ T cells were 76.2%+/-10.4%, 66.5%+/-15.4% and 49.5%+/-25.3% respectively (week 24 vs week 0, P < 0.01; week 12 vs week 0, P < 0.05; week 24 vs week 12, P < 0.05); HBV-specific CD8 cells were 1.3%+/-0.5%, 1.5%+/-1.0% and 2.2%+/-1.5%; IFNgamma levels in cell culture medium were (91.7+/-82.1) pg/ml, (99.4+/-93.5) pg/ml and (109.5+/-86.6) pg/ml. A remarkable decrease of PD-1 and PD-L1 expressions and increase of HBV-specific CD8+ T cells were observed in patients who had HBeAg/HBeAb seroconversion at week 24.
CONCLUSIONSDirect suppression of HBV replication by telbivudine in CHB patients can decrease PD-1 and PD-L1 expressions and restore HBV-specific CD8+T cells. The relationship between the changes of PD-1 expression and HBeAg/HBeAb seroconversion during antiviral therapy in HBeAg-positive patients need to confirm by future study.
Adult ; Antiviral Agents ; therapeutic use ; B7-H1 Antigen ; metabolism ; CD8-Positive T-Lymphocytes ; immunology ; Female ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; genetics ; Hepatitis B, Chronic ; drug therapy ; metabolism ; Humans ; Male ; Nucleosides ; therapeutic use ; Programmed Cell Death 1 Receptor ; metabolism ; Pyrimidinones ; therapeutic use ; Thymidine ; analogs & derivatives ; Young Adult
10.GM-CSF gene-modified dendritic cell vaccine enhances antitumor immunity in vitro.
Song-Bing HE ; Kang SUN ; Liang WANG ; De-Chun LI ; Yan-Yun ZHANG
Chinese Journal of Oncology 2010;32(6):410-414
OBJECTIVETo investigate if granulocyte-macrophage colony stimulating factor (GM-CSF) gene-modified dendritic cells (DC) enhance antitumor immunity in vitro.
METHODSMice were injected with chemokine ligand 3 (CCL3) via the tail vein. Fresh B220(-)CD11c(+) cells were sorted from the peripheral blood mononuclear cells (PBMCs) and cultured into DCs by cytokines.DCs were transfected with AdGM-CSF gene at different ratios of multiplicity of infection (MOI) to determine the optimal gene transfection conditions, and the expression of GM-CSF was detected after transfection. The variation of GM-CSF gene-modifiedDCs were analyzed by morphological examination, phenotype analysis, and mixed lymphocyte reaction (MLR).DCs were loaded with gastric cancer antigen obtained by freezing and thawing method. The killing effect of DCs vaccine-stimulated T lymphocytes on gastric cancer cells was assessed by MTT assay. INF-gamma production was determined with the INF-gamma ELISA kit.
RESULTSB220(-)CD11c(+) cells increased obviously after CCL3 injection. The ELISA results showed that after GM-CSF gene modification, DCs could produce high level of GM-CSF. When DCs were transfected with AdGM-CSF gene at MOI equal to 100, the GM-CSF level in culture supernatants reached saturation [(130.00 +/- 12.61) pg/ml]. After GM-CSF gene-modification, DCs tend to be more maturated as detected by morphological observation and phenotype analysis. At the same time, the capacity of activating the proliferation of allogeneic T lymphocytes was enhanced greatly. T lymphocytes stimulated by DCs transfected with GM-CSF gene showed a specific killing effect on gastric carcinoma cells and produced high level of INF-gamma [(1245.00 +/- 13.75) pg/ml].
CONCLUSIONAfter GM-CSF gene modification, DCs can produce high level of GM-CSF, which tend to be more maturated, and the capacity of activating the proliferation of allogeneic T lymphocytes is enhanced greatly. GM-CSF gene modified DCs can induce specific CTL to target tumor cells in vitro.
Adenoviridae ; genetics ; Animals ; B7-1 Antigen ; metabolism ; B7-2 Antigen ; metabolism ; CD40 Antigens ; metabolism ; Cancer Vaccines ; immunology ; Cell Line, Tumor ; Cell Proliferation ; Cytotoxicity, Immunologic ; Dendritic Cells ; cytology ; immunology ; metabolism ; Female ; Granulocyte-Macrophage Colony-Stimulating Factor ; genetics ; metabolism ; Histocompatibility Antigens Class II ; metabolism ; Interferon-gamma ; secretion ; Mice ; Mice, Inbred BALB C ; Recombinant Proteins ; Stomach Neoplasms ; immunology ; metabolism ; pathology ; T-Lymphocytes, Cytotoxic ; cytology ; immunology ; Transfection

Result Analysis
Print
Save
E-mail