Clin Cancer Res. 2001 Aug;7(8):2277-84.
Dendritic cell vaccination with MAGE peptide is a novel therapeutic approach for gastrointestinal carcinomas.
1Department of Surgery, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu 874-0838, Japan.
The MAGE gene is selectively expressed in cancer tissues such as melanoma or gastrointestinal carcinomas, whereas no expression is observed in normal tissues except testis. There are several reports of successful induction of HLA class I-restricted antitumor CTLs using MAGE peptides, and some clinical trials with these immunogenic peptides were reported as effective for some patients with malignant melanoma. However, there are no similar studies in gastrointestinal carcinomas, which are important neoplasms. Autologous dendritic cells (DCs) were generated ex vivo and were pulsed with MAGE-3 peptide, depending on the patient’s HLA haplotype (HLA-A2 or A24). Patients were immunized with DC pulsed with MAGE-3 peptide every 3 weeks at four times. Twelve patients with advanced gastrointestinal carcinoma (six stomach, three esophagus, and three colon) were treated, and no toxic side effects were observed. Peptide-specific CTL responses after vaccination were observed in four of eight patients. Improvement in performance status was recognized in four patients. Tumor markers decreased in seven patients. In addition, minor tumor regressions evidenced by imaging studies were seen in three patients. These results suggested that DC vaccination with MAGE-3 peptide is a safe and promising approach in the treatment of gastrointestinal carcinomas.
J Exp Clin Cancer Res. 2010 Apr 27;29:37. doi: 10.1186/1756-9966-29-37.
CCL3 and CCL20-recruited dendritic cells modified by melanoma antigen gene-1 induce anti-tumor immunity against gastric cancer ex vivo and in vivo.
1Department of General Surgery, the First Affiliated Hospital of Soochow University, 215006 Suzhou, Jiangsu Province, China.
To investigate whether dendritic cell (DC) precursors, recruited by injection of chemokine ligand 3 (CCL3) and CCL20, induce anti-tumor immunity against gastric cancer induced by a DC vaccine expressing melanoma antigen gene-1 (MAGE-1) ex vivo and in vivo.
B6 mice were injected with CCL3 and CCL20 via the tail vein. Freshly isolated F4/80-B220-CD11c+ cells cultured with cytokines were analyzed by phenotype analysis and mixed lymphocyte reaction (MLR). For adenoviral (Ad)-mediated gene transduction, cultured F4/80-B220-CD11c+ cells were incubated with Ad-MAGE-1. Vaccination of stimulated DC induced T lymphocytes. The killing effect of these T cells against gastric carcinoma cells was assayed by MTT. INF-gamma production was determined with an INF-gamma ELISA kit. In the solid tumor and metastases model, DC-based vaccines were used for immunization after challenge with MFC cells. Tumor size, survival of mice, and number of pulmonary metastatic foci were used to assess the therapeutic effect of DC vaccines.
F4/80-B220-CD11c+ cell numbers increased after CCL3 and CCL20 injection. Freshly isolated F4/80-B220-CD11c+ cells cultured with cytokines were phenotyically identical to typical DC and gained the capacity to stimulate allogeneic T cells. These DCs were transduced with Ad-MAGE-1, which were prepared for DC vaccines expressing tumor antigen. T lymphocytes stimulated by DCs transduced with Ad-MAGE-1 exhibited specific killing effects on gastric carcinoma cells and produced high levels of INF-gamma ex vivo. In vivo, tumor sizes of the experimental group were much smaller than both the positive control group and the negative control groups (P < 0.05). Kaplan-Meier survival curves showed that survival of the experimental group mice was significantly longer than the control groups (P < 0.05). In addition, MAGE-1-transduced DCs were also a therapeutic benefit on an established metastatic tumor, resulting in a tremendous decrease in the number of pulmonary metastatic foci.
CCL3 and CCL20-recruited DCs modified by adenovirus-trasnsduced, tumor-associated antigen, MAGE-1, can stimulate anti-tumor immunity specific to gastric cancer ex vivo and in vivo. This system may prove to be an efficient strategy for anti-tumor immunotherapy.
Zhonghua Zhong Liu Za Zhi. 2009 May;31(5):330-4.
[Immune response of melanoma antigen gene-3 modified dendritic cell vaccines in gastric carcinoma].
[Article in Chinese]
1Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
To investigate the anti-gastric carcinoma immunological efficacy of dendritic cells (DC) precursors, that were mobilized into the peripheral blood by injection of macrophage inflammation protein-1 alpha (MIP-1 alpha), and induced by DC vaccine expressing melanoma antigen gene-3 (MAGE-3) ex vivo and in vivo.
615 mice were injected with MIP-1 alpha via the tail vein. Freshly isolated B220(-) CD11c+ cells were cultured with cytokines and assayed by phenotype analysis and mixed lymphocyte reaction (MLR). For adenoviral (Ad)-mediated gene transduction, cultured B220(-) CD11c+cells were incubated with Ad-melanoma antigen gene-3. MIP-1 alpha-mobilized B220(-) CD11c+ cells pulsed MFC cells tumor lysate were used as positive control. The stimulated DC vaccination-induced T lymphocytes, and the killing effect of the T cells on gastric carcinoma cells were assayed by MTT. INF-gamma production was determined with the INF-gamma ELISA kit. To establish the solid tumor model, groups of 615 mice were injected with MFC cells subcutaneously into the abdominal wall. MIP-1 alpha-mobilized DC vaccines expressing MAGE-3 gene were used to immunize the mice after the challenge of MFC cells, then the tumor size and the survival of mice were examined to detect the therapeutic effect of DC vaccines.
B220(-) CD11c+ cells increased obviously after MIP-1 alpha injection, and freshly isolated B220(-) CD11c+ cells cultured with mGM-CSF, IL-4, and mTNF-alpha were phenotypically identical to typical DC, gained the capacity to stimulate allogeneic T cells. These MIP-1 alpha-mobilized DCs were transduced with Ad-MAGE-3, which were prepared for DC vaccines expressing tumor antigen. T lymphocytes stimulated with DC-transduced with Ad-MAGE-3 showed specific killing effect on gastric carcinoma cells and produced high levels of INF-gamma [(1460.00 +/- 16.82) pg/ml]. Five days after the MFC cells challenge, the mice were subsequently injected with DC vaccines. The tumor size of the experimental group was significantly smaller than that in the positive control group and the negative control groups (P<0.01). Kaplan-Meier survival curves showed the survival of the experimental group mice was significantly longer than that of the control groups (P<0.01).
B220(-) CD11c+ DC precursors are rapidly accumulated in the peripheral blood after injection of MIP-1 alpha into mice, which can further differentiate into mature DCs. These MIP-1 alpha-mobilized DCs, when transduced with MAGE-3 gene, can induce specific CTL to gastric carcinoma cells ex vivo, and can generate anti-tumor therapeutic effects on MFC cells loading mice in vivo. The efficiency of anti-tumor therapeutic immunity induced by MIP-1 alpha-mobilized DCs expressing tumor antigen are much more potent than MIP-1 alpha mobilized DCs pulsed MFC cells tumor lysate.