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

• Published in: Human vaccines & immunotherapeutics Vol. 16; no. 12; pp. 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: Journal Article
• Language: English
• Published: United States Taylor & Francis 01-12-2020; Taylor & Francis Group
• Subjects: Cancer vaccine; CD80; CTLA-4; glycosyl phosphatidylinositol anchor; IL-12; immunotherapy; protein transfer; Research Paper; tumor membrane vesicles; protein transfer; Cancer vaccine; tumor membrane vesicles; CD80; immunotherapy; glycosyl phosphatidylinositol anchor; CTLA-4; IL-12
• ISSN: 2164-5515; 2164-554X
• DOI: 10.1080/21645515.2020.1754691

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.