Abstract
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.
Highlights
Chemotherapy remains one of the cornerstones of cancer treatment despite the side-effects associated with treatment
Few studies have tested the combination of chemotherapy with a therapeutic cancer vaccine [12] and we are not aware of any that have analyzed immune responses induced by vaccinations given before, during and after chemotherapy, alongside phenotyping of lymphocyte subsets
Our studies demonstrated that the administration of Modified vaccinia Ankara (MVA)-5T4 in combination with IrMdG and OxMdG chemotherapy regimens was well tolerated and induced 5T4-specific immune responses in the majority of patients
Summary
Chemotherapy remains one of the cornerstones of cancer treatment despite the side-effects associated with treatment. It has been postulated that cytotoxic chemotherapy regimens increase the exposure of tumor antigens to cells of the immune system through the release of tumor cell fragments from dead or dying cells. The failure of this enhanced exposure to tumor antigens to induce an efficacious anti-tumor immune response that can control residual disease may be explained by the immuno-suppressive nature of both the cancer itself and the chemotherapeutic agent. Cancer immunotherapy approaches depend upon the induction of efficacious anti-tumor responses and the generation of long-term memory [2].
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