Comparative Kinetics of Immune Responses and Changes in Cellular Sub-Sets Detected in Colorectal Cancer Patients Vaccinated with MVA-5T4 (TroVax) Administered Alongside Two Different Chemotherapy Regimens

摘要

Modified vaccinia Ankara (MVA) virus encoding the tumor antigen 5T4 (MVA-5T4;TroVax?) has been tested in two open-label phase II studies in metastatic colorectal cancer patients alongside two chemotherapy regimens, 5-fluorouracil, folinic acid and irinotecan (IrMdG) or 5-fluorouracil, folinic acid and oxaliplatin (OxMdG). The aim of this study was to investigate the kinetics of immune responses and changes in cellular sub-sets before, during and after treatment with each chemotherapy regimen. In total, 23 patients received the complete course of treatment which comprised 2 injections before, during and after completion of chemotherapy. Antibody and cellular responses specific for 5T4 and MVA were monitored throughout the study and changes in immune cell subsets were determined. All 23 evaluable patients mounted MVA- and 5T4-specific cellular and/or humoral responses. Patients on both trials showed significant reductions in the numbers of neutrophils and the proportion of regulatory T cells (Treg) within the CD4+ T cell population. Monocyte and NK cell numbers decreased significantly in patients treated with IrMdG but not OxMdG. The largest increase in 5T4-specific cellular responses was observed 2 weeks following the completion of chemotherapy which was coincident with a decrease in Treg levels. Both chemotherapy regimens resulted in a significant decrease in the proportion of peripheral Tregs. Levels of Tregs during chemotherapy showed an inverse correlation with 5T4 cellular responses detected immediately post-chemotherapy. These data may support a rationale for sequencing chemotherapy with immunotherapy strategies at time points when Treg levels are predicted to be low.