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Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade
A A Hurwitz1, B A Foster, E D Kwon
1Cancer Research Laboratory, University of California, Berkeley 94720, USA. hurwitza@mail.upstate.edu
Abstract:
We have previously shown that antibodies to CTLA-4, an inhibitory receptor on T cells, can be effective at inducing regression of transplantable murine tumors. In this study, we demonstrate that an effective immune response against primary prostate tumors in transgenic (TRAMP) mice can be elicited using a strategy that combines CTLA-4 blockade and an irradiated tumor cell vaccine. Treatment of TRAMP mice at 14 weeks of age resulted in a significant reduction in tumor incidence (15% versus control, 75%), as assessed 2 months after treatment. Histopathological analysis revealed that treated mice had a lower tumor grade with significant accumulation of inflammatory cells in interductal spaces when treated with anti-CTLA-4 and a granulocyte-macrophage colony-stimulating factor-expressing vaccine. Vaccination of nontransgenic mice with this regimen resulted in marked prostatitis accompanied by destruction of epithelium, indicating that the immune response was, at least in part, directed against normal prostate antigens. These findings demonstrate that this combinatorial treatment can elicit a potent antiprostate response and suggest potential of this approach for treatment of prostate cancer.
Insights
Combining CTLA-4 blockade with a tumor cell vaccine significantly reduced prostate tumor incidence in mice. This immunotherapy approach shows promise for treating prostate cancer by eliciting a potent anti-prostate immune response.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), an inhibitory T-cell receptor, have demonstrated efficacy in regressing transplantable tumors.
- Prostate cancer remains a significant health concern, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of a combined immunotherapy approach, utilizing CTLA-4 blockade and an irradiated tumor cell vaccine, against primary prostate tumors in TRAMP mice.
- To assess the impact of this combinatorial treatment on tumor incidence, grade, and the associated immune response.
Main Methods:
- Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice were treated at 14 weeks of age with a combination of anti-CTLA-4 antibodies and a granulocyte-macrophage colony-stimulating factor-expressing tumor cell vaccine.
- Tumor incidence was assessed two months post-treatment.
- Histopathological analysis was performed to evaluate tumor grade and inflammatory cell infiltration.
Main Results:
- Treatment significantly reduced prostate tumor incidence in TRAMP mice (15% vs. 75% in controls).
- Histopathology revealed lower tumor grades and increased inflammatory cell accumulation in treated mice.
- In non-transgenic mice, the regimen induced prostatitis with epithelial destruction, suggesting an immune response against normal prostate antigens.
Conclusions:
- The combination of CTLA-4 blockade and a GM-CSF expressing tumor vaccine elicits a potent anti-prostate immune response.
- This combinatorial immunotherapy strategy demonstrates significant potential for the treatment of prostate cancer.
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