Journal
HUMAN VACCINES & IMMUNOTHERAPEUTICS
Volume 16, Issue 12, Pages 3184-3193Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/21645515.2020.1754691
Keywords
Cancer vaccine; immunotherapy; CTLA-4; CD80; IL-12; protein transfer; tumor membrane vesicles; glycosyl phosphatidylinositol anchor
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Funding
- NCI/NIH SBIR Phase I grant [CA176920, CA221559]
- NCI/NIH SBIR Phase II grant [CA176920, CA221559]
- NCI/NIH R01 grant [R01 CA202763]
- Georgia Research Alliance in Atlanta, Georgia
- [R01 CA202763-S]
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Triple-negative breast cancer (TNBC) afflicts women at a younger age than other breast cancers and is associated with a worse clinical outcome. This poor clinical outcome is attributed to a lack of defined targets and patient-to-patient heterogeneity in target antigens and immune responses. To address such heterogeneity, we tested the efficacy of a personalized vaccination approach for the treatment of TNBC using the 4T1 murine TNBC model. We isolated tumor membrane vesicles (TMVs) from homogenized 4T1 tumor tissue and incorporated glycosyl phosphatidylinositol (GPI)-anchored forms of the immunostimulatory B7-1 (CD80) and IL-12 molecules onto these TMVs to make a TMV vaccine. Tumor-bearing mice were then administered with the TMV vaccine either alone or in combination with immune checkpoint inhibitors. We show that TMV-based vaccine immunotherapy in combination with anti-CTLA-4 mAb treatment upregulated immunomodulatory cytokines in the plasma, significantly improved survival, and reduced pulmonary metastasis in mice compared to either therapy alone. The depletion of CD8(+)T cells, but not CD4(+)T cells, resulted in the loss of efficacy. This suggests that the vaccine acts via tumor-specific CD8(+)T cell immunity. These results suggest TMV vaccine immunotherapy as a potential enhancer of immune checkpoint inhibitor therapies for metastatic triple-negative breast cancer.
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