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. In another study, intratumoral delivery of vector mediated interleukin-2 (IL-2) in combination with vaccine results in enhanced T-cell avidity and anti-tumor activity. Systemic IL-2 is currently employed in the therapy of several tumor types, but at the price of often severe toxicities. Local vector mediated delivery of IL-2 at the tumor site may enhance local effector cell activity while reducing toxicity. To examine this, a model using carcinoembryonic antigen transgenic (CEA-Tg) mice bearing established CEA expressing tumors was employed. The vaccine regimen was a subcutaneous prime vaccination with recombinant vaccinia (rV) expressing transgenes for CEA and a triad of costimulatory molecules (TRICOM) followed by intratumoral (i.t.) boosting with rF-CEA/TRICOM. The addition of i.t. delivery of IL-2 via a recombinant fowlpox (rF) IL-2 vector greatly enhanced anti-tumor activity of a recombinant vaccine, resulting in complete tumor regression in 7080% of mice. The anti-tumor activity was shown to be dependent on CD8+ cells and NK1.1+. Cellular immune assays revealed that the addition of rF-IL-2 to the vaccination therapy enhanced CEA-specific tetramer+ cell numbers, cytokine release and CTL lysis of CEA+ targets. Moreover, tumor bearing mice vaccinated with the CEA/TRICOM displayed an antigen cascade, i.e., CD8+ T cell responses to two other antigens expressed on the tumor and not the vaccine: wild type p53 and endogenous retroviral antigen gp70. Mice receiving rF-IL-2 during vaccination demonstrated higher avidity CEA-specific, as well as higher avidity gp70-specific, CD8+ T cells when compared with mice vaccinated without rF-IL-2. These studies demonstrate for the first time that the level and avidity of antigen-specific cytotoxic T lymphocyte (CTL), as well as the therapeutic outcome can be improved with the use of i.t. rF-IL-2 with vaccine regimens. The combined activation of positive costimulatory signals with modulation of a negative costimulatory signal for the enhancement of vaccine mediated T-cell responses. In this study, blockade of CTLA-4 by monoclonal antibodies (mAb) can mediate regression of tumors and increase the efficacy of tumor antigen specific vaccines. Blockade of CTLA-4 has also been shown to significantly increase the avidity of antigen-specific T cells after immunization with live recombinant viral vector based vaccine. Here, we demonstrate a biological synergy between CTLA-4 blockade and active vaccine therapy consisting of recombinant vaccinia and avipox viruses expressing carcinoembryonic antigen (CEA) and three T cell costimulatory molecules to enhance antitumor effects. However, this synergy was very much dependent on the temporal relationship of scheduling of the two agents. We evaluated the strategies in both a foreign antigen model using b-galactosidase as immunogen, and in a self antigen model using CEA as immunogen. For antitumor activity the model used consisted of mice transgenic for human CEA and a murine carcinoma cell line transfected with CEA. The enhanced antitumor activity after vaccine and CTLA-4 blockade did not result in any signs of autoimmunity. These studies form a rational basis for the use of vector-based vaccines with anti-CTLA-4 and demonstrate that both enhancement of positive costimulatory signals and inhibition of negative costimulatory signals can be simultaneously exploited. These studies also underscore the importance of drug scheduling in vaccine combination therapies. Combination therapy of an orthotopic renal cell carcinoma model employing intratumoral vector-mediated costimulation and systemic IL-2. Interleukin (IL)-2 therapy is currently used for therapy of renal cell carcinoma (RCC). However, it is only effective in approximately 10% to 15% of patients, showing a need for additional therapies. We have previously described a replication-defective fowlpox (rF-) vector encoding a triad of costimulatory molecules (B7-1, ICAM-1, and LFA-3), designated rF-TRICOM. These studies demonstrates that intratumoral administration of rF-TRICOM in an orthotopic RCC model effectively enhances tumor immunogenicity and reduces tumor burden in mice and the combination of rF-TRICOM and interleukin-2 (IL-2) is more effective than either therapy alone. RCC cells were implanted under the capsule of the kidney, and mice were given rF-TRICOM intratumorally 14 days later. We compared the effect of rF-TRICOM, rF-granulocyte macrophage colony-stimulating factor (GM-CSF), and two doses of IL-2 and combinations of the above on antitumor efficacy and survival. Host CD4+ and CD8+ T-cell responses were also evaluated. The results show that (a) systemic IL-2 therapy was moderately effective in the reduction of tumor burden in an orthotopic RCC model; (b) a single intratumoral injection of rF-TRICOM and rF-GM-CSF significantly reduced tumor burden; (c) the addition of systemic IL-2 to intratumoral rF-TRICOM/rF-GM-CSF administration resulted in further reduction of tumor burden, decrease in the incidence of metastasis, and extended survival in tumor-bearing mice above that seen ih either treatment alone; and (d) CD8+ T cells played a critical role in the antitumor effect seen with rF-TRICOM/rF-GM-CSF + IL-2 therapy. Finally, the addition of systemic recombinant IL-15 or intratumoral vector-delivered IL-15 to intratumoral rF- TRICOM / rF-GM-CSF administration resulted in substantially more tumor-free mice than either therapy alone. These studies show that intratumoral administration of rF-TRICOM admixed with rF-G [summary truncated at 7800 characters]
Showing the most recent 10 out of 26 publications
