Vaccine and Drug Combination Therapy for Human Cancers

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Recombinant poxviruses expressing tumor-associated antigens (TAAs) are currently being evaluated in clinical trials as an approach to treat various cancers. We have previously generated poxviral vectors expressing a TAA and a TRIad of COstimulatory Molecules (B7-1, ICAM-1, and LFA-3; designated TRICOM) as transgenes, including replication competent recombinant vaccinia (rV) or replication-defective modified vaccinia Ankara (MVA), to prime tumor-specific immune responses, and a replication-defective recombinant fowlpox (rF) to boost these responses. MVA is a potentially safer, replication-defective form of vaccinia virus with unique immuno-stimulatory properties that could make it a superior priming vaccine. Here, an MVA vector encoding a tumor antigen (CEA) and TRICOM was utilized (rMVA). A single rMVA-CEA/TRICOM vaccination induced greater expression of several serum cytokines associated with enhanced T-cell immunity than that seen with vaccinia. We hypothesized that this effect might precondition the vaccination site for a more effective boost. An rMVA-CEA/TRICOM prime followed 7 days later (but not 30 days later) by an rF-CEA/TRICOM boost at the same injection site (but not at a distal site) induced more potent CEA-specific T-cell responses, and superior CEA-specific immunity and antitumor activity, than rV-CEA/TRICOM followed by rF-CEA/TRICOM. This preconditioning effect was also observed using a heterologous antigen model, where priming with rMVA-CEA/TRICOM followed 7 days later by rF-LacZ/TRICOM enhanced-beta-gal-specific immunity compared to rF-LacZ/TRICOM only. These studies show for the first time that priming with rMVA followed 7 days later by an rF boost at the same injection site, versus a distal site, generates superior tumor-specific immunity and antitumor activity. Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement. Taxanes comprise some of the most widely used cancer chemotherapeutic agents. Members of this drug family, including docetaxel, are commonly used to treat breast, prostate, and lung cancers, among others. This study was designed to determine if this taxane has the ability to modulate components of the immune system independent of antitumor activity and to investigate the potential synergistic activities of the combination of docetaxel and vaccine therapy. We examined the in vivo effects of docetaxel on immune-cell subsets and on the function of CD4+, CD8+, and T regulatory cell (Treg cell) populations in response to antigen-specific vaccination. We also examined the antitumor effects of the combination of docetaxel and vaccine in a preclinical model in which docetaxel has no observable effect on tumor growth. These studies show for the first time that (a) docetaxel modulates CD4+, CD8+, CD19+, natural killer cell, and Treg populations in non-tumor-bearing mice; (b) unlike cyclophosphamide, docetaxel does not inhibit the function of Tregs; (c) docetaxel enhances CD8+ but not CD4+ response to CD3 cross-linking; (d) docetaxel given after vaccination provides optimal enhancement of immune response to recombinant viral vaccines; (e) docetaxel combined with recombinant viral vaccine is superior to either agent alone at reducing tumor burden; and (f) docetaxel plus vaccine increases antigen-specific T-cell responses to antigen in the vaccine, as well as to cascade antigens derived from the tumor. These findings suggest potential clinical benefit for the combined use of docetaxel and recombinant cancer vaccines.