Development of a Tumor Membrane-based Vaccine for Breast Cancer, Studied as a Monotherapy and in Combination with Immune Checkpoint Blockade Antibodies Open Access

Vartabedian, Vincent Frank (2015)

Permanent URL: https://etd.library.emory.edu/concern/etds/mc87pq769?locale=en
Published

Abstract

1 in 8 women will be diagnosed with breast cancer in her lifetime, and the five year survival rate for patients diagnosed with stage III or IV breast cancer is only 25%, due to metastasis. Chemotherapy serves as the primary standard of care to treat metastatic growth. However, chemotherapy can cause severe side effects due to its non-specific nature, and, likely due to inter-personal and intra-tumoral heterogeneity, its efficacy is lacking. Here, we propose the use of a personalized tumor membrane vesicle (TMV) based vaccine made from autologous tumor cells and decorated with GPI-anchored IL-12 and B7-1 via a simple protein transfer method, and we evaluate its efficacy alone and in combination with immune checkpoint blockade antibodies against CTLA-4 and PD-L1 in 4TO7 and E0771 breast cancer settings. We show that our modified TMV vaccine reduces tumor burden as a monotherapy in the 4TO7 system, but do not find statistically significant differences in efficacy in either combination therapy setting. Perhaps due to immune checkpoint upregulation, we do not see efficacy of our vaccine in the E0771 setting.

Table of Contents

Abbreviations Used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Materials and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Financial & competing interest disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Appendix A: Publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

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