As a means to increase antigen processing and expression in APCs and improve the expression of costimulatory molecules, recombinant viral-based vaccines have been developed. The pox virus family has been most commonly used (vaccinia, fowlpox) but others such as adenovirus have been used. Genes encoding TAAs are genetically recom-bined to the virus and then administered. The virus serves as a vector, infecting cells including APCs; the passenger gene is then transcribed and translated into a full-length protein, then cleaved into smaller peptides (9-10 amino acids in length for major histocompatibility complex [MHC] class I, 13-15 amino acids for MHC class II presentation) and then presented on the cell surface in the context of appropriate costimulatory molecules to activate both CD4 and CD8 T cells (13).
Phase I clinical trials have been completed for both vaccinia-CEA (14,15) and ALVAC-CEA (16). These trials both demonstrated significant generation of CEA-specific cytotoxic T lymphocytes (CTLs) that were capable of lysing autologous (and allogeneic) tumor. The vaccines were well tolerated without significant toxicity. Vaccinia was found to be a potent stimulus upon initial vaccination but subsequent injections added little. It is important to note that all patients on this trial had received prior vaccinia vaccinations, which may of course have influenced the outcomes. Fowlpox, on the other hand, was less potent but immune responses measured as CEA-specific T cells increased with each injection. This suggests that fowlpox-CEA could serve as an effective booster to the immune response.
Based on this clinical experience and strong preclinical data (17,18), a trial combining vaccinia-CEA (V) and fowlpox-CEA (F) was preformed. In the first stage of this trial, patients with CEA-bearing cancers were randomly assigned to receive either V-F-F-F or
F-F-F-V (19). Both safety and immune response were end points. The vaccines were very safe with virtually no toxicity observed that was attributable to the vaccines. In addition, the immune response data as measured using ELISPOT analyses of CAP-1 T cells demonstrated a significantly greater response for patients receiving V-F-F-F as compared to the other sequence. Supporting the clinical relevance of this immune data was the observation that the V-F-F-F group had a significantly longer survival than those randomized to the other arm. Therefore, the clinical data corroborated the preclinical data suggesting that the "prime and boost" schedule was superior to one vaccine alone. This conclusion remains controversial and further studies are required to confirm this finding. Though recent global events have made us less concerned about using vaccinia as a viral vector for vaccines, we must recognize that there is a known life-threatening toxicity associated with vaccinia. Therefore, we must be certain of its importance as we go forward.
Several clinical trials have followed on the above prime-and-boost trial. The first was the serial addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-2 along with the vaccines (20). Presented in abstract form, the results showed that GM-CSF did generate a greater T-cell response compared to vaccines alone and clinical benefit was seen in several patients including a complete tumor response. However these patients were not randomized. The IL-2 group did not show any further advantage over the GM-CSF group and did experience a higher degree of toxicity associated with the IL-2.
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