4-1BB ligand enhances tumor-specific immunity of poxvirus vaccines

Abstract

Purpose-Recombinant poxvirus vaccines have been explored as tumor vaccines. The immunogenicity of these vaccines can be enhanced by co-expressing costimulatory molecules and tumor-associated antigens. While the B7-CD28 interaction has been most comprehensively investigated, other costimulatory molecules utilize different signaling pathways and might provide further cooperation in T cell priming and survival. 4-1BB (CD137) is a TNF family member and is critical for activation and long-term maintenance of primed T-cells. This study was conducted to determine if a poxvirus expressing the ligand for 4-1BB (4-1BBL) could further improve the immune and therapeutic responses of a previously reported poxvirus vaccine expressing a triad of costimulatory molecules (B7.1, ICAM-1, and LFA-3).Experimental Design-A recombinant vaccinia virus expressing 4-1BBL was generated and characterized in an in vitro infection system. This vaccine was then used alone or in combination with a vaccinia virus expressing CEA, B7.1, ICAM-1, and LFA-3 in CEA-transgenic mice bearing established MC38 tumors. Tumor growth and immune responses against CEA and other tumorassociated antigens were determined. The level of anti-apoptotic proteins in responding T cells was determined by flow cytometry on tetramer selected T cells.Results-The combination of 4-1BBL with B7.1-based poxvirus vaccination resulted in significantly enhanced therapeutic effects against CEA-expressing tumors in a CEA transgenic mouse model. This was associated with an increased level of CEA-specific CD4 + and CD8 + T cell responses, induction of antigen spreading to p53 and gp70, increased accumulation of CEA-specific T cells in the tumor microenvironment, and increased expression of bcl-XL and bcl-2 in CD4 + and CD8 + T cells in vaccinated mice. Conclusion-4-1BBLcooperates with B7 in enhancing anti-tumor and immunologic responses using a recombinant poxvirus vaccine model. The inclusion of costimulatory molecules targeting distinct T cell signaling pathways provides a mechanism for enhancing the therapeutic effectiveness of tumor vaccines.

Host Lymphodepletion Enhances the Therapeutic Activity of an Oncolytic Vaccinia Virus Expressing 4-1BB Ligand

“…Recombinant viruses. rV-4-1BBL and rV-LacZ were constructed as described previously (21). All viruses were propagated in BS-C-1 cells and purified on a sucrose gradient by ultracentrifugation.…”

“…Finally, we have previously shown that an oncolytic vaccinia virus expressing 4-1BBL had significant antitumor activity in a carcinoembryonic antigen transgenic murine carcinoma model. Furthermore, the rV-4-1BBL resulted in antigen spreading and a significant increase in tumor antigen-specific T cells within the tumor microenvironment of regressing tumors (21).…”

Induction of Antitumor Immunity Ex Vivo Using Dendritic Cells Transduced With Fowl Pox Vector Expressing MUC1, CEA, and a Triad of Costimulatory Molecules (rF-PANVAC)

“…As such, a prime/boost strategy involving sequential vaccination with vaccinia and fowl pox vectors, respectively has been shown to generate more durable antigen specific responses(3). In addition, insertion of genes coding for the costimulatory and adhesion molecules, CD80 (B7.1), CD54 (ICAM-1) and CD58 (LFA-3) (designated TRICOM) and the ligand binding 4-1BB further enhances immunologic response (4). In clinical studies, vaccination with pox viruses expressing tumor associated antigens has resulted in immunologic responses in a subset of patients (5–6).…”

4-1BB and the Epigenetic Regulations of This Molecule

“…4-1BB, 4-1BBL and these antibodies are used to enhance the defense system of the body against pathogens [16] and to improve the vaccine effect [17,18,19]. The combination of 4-1BB antibodies with other reagents and methods to prevent diseases brings some positive results, such as the combination with IL-12 or histone deacetylase inhibitors (HDACi) in tumor treatment [20,21].…”