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Combinational immunotherapy for established tumors with engineered tumor vaccines and adenovirus-mediated gene
1Departments of Microbiology, Saskatoon Cancer Center, University of Saskatchewan, Saskatoon, Canada.
Abstract:
There are currently extensive studies relating to cancer vaccines using tumor cells engineered to express immunogenes and cancer gene therapy using adenovirus (AdV)-mediated gene transfer. In this study, a mouse tumor cell line, VKCK, was cotransfected with genes coding for tumor necrosis factor-alpha (TNF-alpha) and costimulatory B7-1 molecule to enhance immunogenicity. The transfectant cell line VKCK-TNF-alpha/B7-1 showed reduced tumorigenicity and tumor regression. Its inoculation further induced protective immunity; both CD4+ and CD8+ T cells were involved in the induction phase, whereas only CD8+ T cells mediated the effector phase. Susceptible mice bearing VKCK tumors developed a T helper type 2-dominant response, whereas resistant mice with VKCK-TNF-alpha/B7-1 tumor regression developed a T helper type 1-dominant response to VKCK, indicating that the tumor regression was related to a shift in the cytokine profile of the host from type 2 to type 1. Vaccination of VKCK-TNF-alpha/B7-1 cells inhibited tumor formation derived from a single dose of 3 x 10(6) VKCK cells and eradicated 3-day tumors but not 10-day tumors. AdV-mediated TNF-alpha gene transfer by intratumoral injection of AdV-TNF-alpha significantly inhibited tumor growth but failed to eradicate any well-established tumors. However, combinational immunotherapy with vaccination of VKCK-TNF-alpha/B7-1 cells and AdV-mediated TNF-alpha gene transfer not only significantly inhibited tumor growth but also eradicated 10-day VKCK tumors in three of eight mice. Therefore, the present study may be useful not only in understanding the mechanisms responsible for an efficient antitumoral immunity, but also in establishing a more effective immunotherapeutic approach for cancer patients.
Insights
Engineered cancer vaccines combining tumor necrosis factor-alpha (TNF-alpha) and B7-1 enhanced immunogenicity, leading to tumor regression and protective immunity. Combining this with adenovirus-mediated TNF-alpha gene transfer eradicated established tumors, offering a promising cancer immunotherapy approach.
Area of Science:
- Immunology
- Cancer Research
- Gene Therapy
Background:
- Extensive research exists on cancer vaccines using engineered tumor cells and adenovirus (AdV)-mediated gene transfer for cancer gene therapy.
- Enhancing tumor cell immunogenicity is crucial for effective cancer immunotherapy.
Purpose of the Study:
- To investigate the efficacy of cotransfecting mouse tumor cells (VKCK) with tumor necrosis factor-alpha (TNF-alpha) and B7-1 genes to enhance immunogenicity.
- To evaluate the therapeutic potential of combining engineered tumor cell vaccination with AdV-mediated TNF-alpha gene transfer for cancer treatment.
Main Methods:
- VKCK mouse tumor cells were cotransfected with TNF-alpha and B7-1 genes, creating the VKCK-TNF-alpha/B7-1 cell line.
- Assessed tumor growth, regression, and protective immunity induction following inoculation of engineered cells.
- Utilized AdV-mediated TNF-alpha gene transfer and evaluated combinational immunotherapy effects on established VKCK tumors.
Main Results:
- VKCK-TNF-alpha/B7-1 cells exhibited reduced tumorigenicity and induced tumor regression and protective immunity involving CD4+ and CD8+ T cells.
- Tumor regression correlated with a shift from a T helper type 2 to a T helper type 1 dominant immune response.
- Combinational therapy significantly inhibited tumor growth and eradicated established 10-day tumors in a subset of mice.
Conclusions:
- Engineering tumor cells with TNF-alpha and B7-1 enhances immunogenicity and therapeutic potential.
- A shift towards a T helper type 1 response is critical for tumor regression.
- Combinational immunotherapy represents a promising strategy for developing more effective cancer treatments.