Tumor membrane-based vaccine immunotherapy in combination with anti-CTLA-4 antibody confers protection against immune checkpoint resistant murine triple-negative breast cancer

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 addre...

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Bibliographic Details
Published in:Human vaccines & immunotherapeutics 2020-12, Vol.16 (12), p.3184-3193
Main Authors: Pack, Christopher D., Bommireddy, Ramireddy, Munoz, Luis E., Patel, Jaina M., Bozeman, Erica N., Dey, Paulami, Radhakrishnan, Vijayaraghavan, Vartabedian, Vincent F., Venkat, Kalpana, Ramachandiran, Sampath, Reddy, Shaker J. C., Selvaraj, Periasamy
Format: Article
Language:English
Subjects:
Cancer vaccine
CD80
CTLA-4
glycosyl phosphatidylinositol anchor
IL-12
immunotherapy
protein transfer
Research Paper
tumor membrane vesicles
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Summary: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.
ISSN:2164-5515
2164-554X
DOI:10.1080/21645515.2020.1754691