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Generation of a Novel Dendritic-cell Vaccine Using Melanoma and Squamous Cancer Stem Cells
Published on: January 6, 2014
Dendritic cell-based full-length survivin vaccine in treatment of experimental tumors
Srinivas Nagaraj1, Vladimir Pisarev, Leo Kinarsky
1H. Lee Moffitt Cancer Center and Department of Interdisciplinary Oncology, University of South Florida, Tampa, FL 33612 , USA.
Abstract:
Survivin is a good candidate for cancer immunotherapy since it is overexpressed in most common human cancers, poorly expressed in most normal adult tissues and is essential for cancer cell survival. Previously, we and others have demonstrated that survivin-specific immune responses can be generated in mice and cancer patients. These responses resulted in a substantial antitumor effect. However, the fact that survivin is expressed in normal hematopoietic progenitor cells and endothelial cells may potentially limit the use of vaccination against survivin in the clinic due to possible toxicity. In this study, we have evaluated this risk by using dendritic cells (DC) transduced with an adenovirus encoding mutant human survivin (Ad-surv DCs). Immunization of mice with Ad-surv DCs resulted in generation of CD8 T cells recognizing multiple epitopes from mouse survivin. These responses provided significant antitumor effect against 3 different tumors EL-4 lymphoma, MC-38 carcinoma, and MethA sarcoma. Survivin-specific T-cells did not affect bone marrow hematopoietic progenitor cells and no autoimmune abnormalities were observed. However, as was the case with other tumor vaccines it provided only partial antitumor effect against established tumors. The existing paradigm suggests that generation of immune response against multiple tumor-associated antigens may provide a better antitumor effect. Here, we directly tested this hypothesis by combining vaccines targeting different tumor-associated proteins: survivin and p53. Despite the fact that combination of 2 vaccines generated potent antigen specific T-cell responses against both molecules they did not result in the improvement of antitumor effect in any of the tested experimental tumor models.
Insights
Cancer immunotherapy using survivin shows promise, with survivin-specific T-cells demonstrating antitumor effects without harming normal cells. Combining survivin and p53 vaccines did not enhance this antitumor activity.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Survivin is a promising cancer immunotherapy target due to its overexpression in cancers and essential role in cancer cell survival.
- Previous studies show survivin-specific immune responses can generate antitumor effects.
- Potential toxicity due to survivin expression in normal hematopoietic progenitor cells and endothelial cells needs evaluation.
Purpose of the Study:
- To evaluate the risk of survivin-targeted cancer immunotherapy using dendritic cells (DC) transduced with an adenovirus encoding mutant human survivin (Ad-surv DCs).
- To assess the antitumor effect and potential toxicity of Ad-surv DCs immunization.
- To test the hypothesis that combining vaccines targeting multiple tumor-associated antigens (survivin and p53) improves antitumor effects.
Main Methods:
- Mice were immunized with Ad-surv DCs.
- CD8 T cell responses against mouse survivin epitopes were analyzed.
- Antitumor effects were tested against EL-4 lymphoma, MC-38 carcinoma, and MethA sarcoma.
- Combination therapy with survivin and p53 vaccines was evaluated.
Main Results:
- Ad-surv DCs immunization generated CD8 T cells recognizing multiple mouse survivin epitopes.
- Significant antitumor effects were observed against three different tumors.
- Survivin-specific T-cells did not affect bone marrow hematopoietic progenitor cells, and no autoimmune abnormalities were observed.
- Combination therapy with survivin and p53 vaccines did not improve antitumor effects despite generating potent antigen-specific T-cell responses.
Conclusions:
- Vaccination with Ad-surv DCs is a safe approach for generating survivin-specific CD8 T cells with antitumor activity.
- Targeting survivin alone or in combination with p53 did not overcome limitations in treating established tumors.
- Further strategies are needed to enhance the efficacy of cancer immunotherapy against established tumors.
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