Neoadjuvant anti-tumor vaccination prior to surgery enhances survival

Abstract

Background: This study was conducted to determine if anti-tumor vaccination administered prior to partial debulking surgery could improve survival using a murine solid tumour model. Methods: Tumor incidence and survival rates were compared in mice bearing subcutaneous AB1-HA mesothelioma tumors that received either sham surgery, debulking surgery or vaccination prior to debulking surgery. Additionally, mice were depleted of CD4 and/or CD8 T lymphocytes during vaccination to assess their involvement in vaccine induced anti-tumor immunity. Flow cytometry was performed to characterise changes in the proportion and activation status of immune cells associated with anti-tumor immunity. Results: Neoadjuvant vaccination combined with debulking surgery resulted in decreased tumor burden, increased survival and generation of tumor-specific immunity compared to surgery alone. Depletion of CD8 T cells completely abrogated any vaccine induced anti-tumor immune response. Conversely, CD4 depletion enhanced CD8 T cell activation resulting in complete tumor regression in 70% of mice treated with combined surgery and vaccination therapy. Tumor free survival was associated with established immunological memory as defined by the induction of effector memory T cells and resistance to rechallenge with parental AB1 mesothelioma cells. Conclusions: Neoadjuvant anti-cancer vaccination combined with partial debulking surgery induced CD8-dependent anti-tumor immunity that significantly delayed tumor outgrowth relative to surgery alone. Complete tumor eradication was observed when vaccination and surgery were performed in CD4 T cell depleted animals. This demonstrates that adjuvant immunotherapy can improve post-surgical survival following cancer debulking surgery and provides a scientific rational for clinical trials of such an approach.