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Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Whole cell vaccination using immunogenic cell death by an oncolytic adenovirus is effective against a colorectal
Tomoki Yamano1, Shuji Kubo2, Miki Fukumoto1
1Division of Lower Gastrointestinal Surgery, Department of Surgery , Hyogo College of Medicine , Nishinomiya, Japan.
Abstract:
Cancer vaccine application is limited to specific cancer types because few cancer-associated antigens are known to induce tumor rejection. Accordingly, we assessed the utility of Ad881, an oncolytic adenovirus in which viral replication was strictly regulated by the cancer-specific midkine promoter, as a cancer vaccine in a murine colorectal cancer model lacking specific cancer-associated antigens. In CT26 and CMT93 cells, Ad881 (multiplicity of infection: 100 or 1,000) showed stronger cytotoxicity and oncolysis in vitro than its equivalent replication-defective adenovirus, Ad884. CT26 cells (1 × 104) infected with Ad881 (multiplicity of infection: 1,000) for 24 hours were suitable as vaccine antigens without tumor formation in our model. Repeated vaccinations, but not single vaccination, induced a greater prophylactic immune response. The percentage of mice that rejected the tumor challenge was 0, 4, and 38% after no vaccination, single vaccination, and repeated vaccinations, respectively. Immunogenic cell death marker high-mobility group box 1 protein (HMGB1) and adenosine triphosphate in culture medium were higher after Ad881 infection (24.3 ng/ml and 48.2 nmol/l, respectively) than after Ad884 infection (8.6 ng/ml and 15.4 nmol/l, respectively) or oxaliplatin treatment (3.7 ng/ml and 1.8 nmol/l, respectively). These results indicate that repeated whole cell vaccination using an oncolytic adenovirus may be a potent approach to evoke immunogenic cell death.
Insights
Repeated vaccination with Ad881, an oncolytic adenovirus, effectively induced tumor rejection in a colorectal cancer model by promoting immunogenic cell death. This approach shows promise for cancer vaccine development.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Cancer vaccine efficacy is limited by the scarcity of known tumor-rejection antigens.
- Oncolytic viruses offer a novel platform for cancer therapy and vaccination.
Purpose of the Study:
- To evaluate Ad881, a midkine promoter-regulated oncolytic adenovirus, as a cancer vaccine in a murine colorectal cancer model.
- To assess the potential of Ad881 to induce immunogenic cell death and a prophylactic immune response.
Main Methods:
- Ad881 and Ad884 (replication-defective control) were tested for cytotoxicity and oncolysis in CT26 and CMT93 cancer cells.
- CT26 cells infected with Ad881 were used as vaccine antigens in a murine colorectal cancer model.
- Tumor challenge was performed after single or repeated vaccination protocols.
- Levels of high-mobility group box 1 protein (HMGB1) and adenosine triphosphate were measured as markers of immunogenic cell death.
Main Results:
- Ad881 demonstrated superior cytotoxicity and oncolysis compared to Ad884 in vitro.
- Ad881-infected CT26 cells served as effective vaccine antigens without causing tumor formation.
- Repeated vaccinations significantly enhanced tumor rejection rates (38%) compared to single vaccination (4%) or no vaccination (0%).
- Ad881 infection led to higher levels of HMGB1 and ATP, indicating increased immunogenic cell death.
Conclusions:
- Repeated whole-cell vaccination using Ad881, an oncolytic adenovirus, is a potent strategy for inducing immunogenic cell death.
- This approach holds significant potential for developing effective cancer vaccines, particularly in models lacking specific cancer antigens.
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