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Active immunotherapy of cancer with a nonreplicating recombinant fowlpox virus encoding a model tumor-associated
1Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD 20814, USA.
Abstract:
Some tumor cells express Ags that are potentially recognizable by T lymphocytes and yet do not elicit significant immune responses. To explore new immunotherapeutic strategies aimed at enhancing the recognition of these tumor-associated Ags (TAA), we developed an experimental mouse model consisting of a lethal clone of the BALB/c tumor line CT26 designated CT26.WT, which was transduced with the lacZ gene encoding beta-galactosidase, to create CT26.CL25. The growth rate and lethality of CT26.CL25 and CT26.WT were virtually identical despite the expression by CT26.CL25 of the model tumor Ag in vivo. A recombinant fowlpox virus (rFPV), which is replication incompetent in mammalian cells, was constructed that expressed the model TAA, beta-galactosidase, under the influence of the 40-kDa vaccinia virus early/late promoter. This recombinant, FPV.bg40k, functioned effectively in vivo as an immunogen, eliciting CD8+ T cells that could effectively lyse CT26.CL25 in vitro. FPV.bg40k protected mice from both subcutaneous and intravenous tumor challenge by CT26.CL25, and most surprisingly, mice bearing established 3-day pulmonary metastasis were found to have significant, Ag-specific decreases in tumor burden and prolonged survival after treatment with the rFPV. These observations constitute the first reported use of rFPV in the prevention and treatment of an experimental cancer and suggest that changing the context in which the immune system encounters a TAA can significantly and therapeutically alter the host immune response against cancer.
Insights
This study introduces a novel approach using recombinant fowlpox virus (rFPV) to enhance anti-tumor immunity. The rFPV effectively generated CD8+ T cells, leading to reduced tumor burden and improved survival in a mouse cancer model.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Tumor cells can express antigens (Ags) that T lymphocytes recognize but fail to mount a significant immune response.
- Exploring novel immunotherapeutic strategies is crucial for enhancing the recognition of tumor-associated antigens (TAA).
Purpose of the Study:
- To develop and evaluate a recombinant fowlpox virus (rFPV) expressing a model TAA for cancer immunotherapy.
- To investigate the efficacy of rFPV in preventing and treating experimental cancer by altering the immune response context.
Main Methods:
- Created a mouse model (CT26.CL25) expressing beta-galactosidase as a model TAA.
- Constructed a replication-incompetent rFPV (FPV.bg40k) encoding beta-galactosidase.
- Assessed the immunogenicity and anti-tumor effects of FPV.bg40k in vivo and in vitro.
Main Results:
- FPV.bg40k elicited CD8+ T cells capable of lysing tumor cells.
- The rFPV demonstrated protection against both subcutaneous and intravenous tumor challenges.
- Treatment with FPV.bg40k significantly reduced tumor burden and prolonged survival in mice with established pulmonary metastasis.
Conclusions:
- This study reports the first use of rFPV for cancer prevention and treatment in an experimental setting.
- Altering the context of TAA presentation to the immune system can therapeutically enhance anti-cancer immune responses.