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Dendritic cell-based vaccination combined with gemcitabine increases survival in a murine pancreatic carcinoma model.
Background: Tumor-specific cytotoxic T lymphocytes (CTL) can be activated in vivo by
vaccination with dendritic cells (DC). However, clinical responses to DC-based vaccination
have only been observed in a minority of patients with solid cancer. Combination with other
treatment modalities such as chemotherapy may overcome immunoresistance of cancer
cells. We have previously shown that gemcitabine sensitizes human pancreatic carcinoma
cells against CTL-mediated lysis. Here, we used a murine pancreatic carcinoma model to
investigate whether combination with gemcitabine increases therapeutic efficacy of DCbased
vaccination. Methods: Bone marrow-derived DC from C57BL/6 mice were loaded with
UV-irradiated, syngeneic Panc02 carcinoma cells and were administered subcutaneously.
For prophylactic vaccination, mice were vaccinated three times in weekly intervals prior to
tumor challenge with Panc02 cells. Therapeutic vaccination was started when tumors formed
a palpable nodule. Gemcitabine was administered intraperitoneally twice weekly. Results:
Prophylactic DC-based vaccination completely prevented subcutaneous and orthotopic
tumor development and induced immunological memory as well as tumor antigen-specific
CTL. In the subcutaneous tumor model, therapeutic DC-based vaccination was equally
effective as gemcitabine (14 % vs. 17 % survival at day 58 after tumor challenge; controls: 0
%). Combination of the two strategies significantly increased survival of tumor-bearing mice
(50 % at day 58 after tumor challenge). DC-based vaccination also prevented death from
pulmonary metastatization after i.v.-injection of Panc02 cells. Conclusion: DC-based
immunotherapy may not only be successfully combined with gemcitabine for the treatment of
advanced pancreatic carcinoma, but may also be effective in preventing local recurrence or
metastatization in tumor-free patients.
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By Ludwig-Maximilians-Universität MünchenBackground: Tumor-specific cytotoxic T lymphocytes (CTL) can be activated in vivo by
vaccination with dendritic cells (DC). However, clinical responses to DC-based vaccination
have only been observed in a minority of patients with solid cancer. Combination with other
treatment modalities such as chemotherapy may overcome immunoresistance of cancer
cells. We have previously shown that gemcitabine sensitizes human pancreatic carcinoma
cells against CTL-mediated lysis. Here, we used a murine pancreatic carcinoma model to
investigate whether combination with gemcitabine increases therapeutic efficacy of DCbased
vaccination. Methods: Bone marrow-derived DC from C57BL/6 mice were loaded with
UV-irradiated, syngeneic Panc02 carcinoma cells and were administered subcutaneously.
For prophylactic vaccination, mice were vaccinated three times in weekly intervals prior to
tumor challenge with Panc02 cells. Therapeutic vaccination was started when tumors formed
a palpable nodule. Gemcitabine was administered intraperitoneally twice weekly. Results:
Prophylactic DC-based vaccination completely prevented subcutaneous and orthotopic
tumor development and induced immunological memory as well as tumor antigen-specific
CTL. In the subcutaneous tumor model, therapeutic DC-based vaccination was equally
effective as gemcitabine (14 % vs. 17 % survival at day 58 after tumor challenge; controls: 0
%). Combination of the two strategies significantly increased survival of tumor-bearing mice
(50 % at day 58 after tumor challenge). DC-based vaccination also prevented death from
pulmonary metastatization after i.v.-injection of Panc02 cells. Conclusion: DC-based
immunotherapy may not only be successfully combined with gemcitabine for the treatment of
advanced pancreatic carcinoma, but may also be effective in preventing local recurrence or
metastatization in tumor-free patients.
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