Blood, 1 November 2004, Vol. 104, No. 9, pp. 2612-2613.
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GENE THERAPY
Comment on Tang et al, page 2704
Your Ad here: optimizing adenoviral vector-based vaccines
H. Kim Lyerly
DUKE COMPREHENSIVE CANCER CENTER
Tang and colleagues extend their studies of a recombinant adenoviral vector encoding a tumor-associated antigen fused to the CD40 ligand, and report of the multistep process through which this vaccine overcomes anergy to tumor associated antigens.
Viral infections often lead to "effective" immune responses, often neutralizing free virus, eradicating virally infected cells, and preventing further viral replication. The robustness of this immune response has led cancer immunologists to generate recombinant viral vectors encoding tumor-associated antigens (TAAs) of interest to be used in preventive and therapeutic cancer vaccines. Unfortunately, some viruses use stealthlike strategies to circumvent effective immune responses, allowing them to persistently reside in the host; furthermore, the viral-specific immune response may be central to the chronic pathophysiology of the infection. Therefore, alternatives to simply using parental recombinant viral vectors are being actively explored. One promising strategy is to include human genes encoding proteins critical to enhancing immune response. For example, Schlom and colleagues (Hodge et al1) have generated recombinant vaccinia and fowlpox-based vaccines that encode a combination of membrane-based costimulatory molecules including B7-1 (CD80), intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated antigen 3 (LFA-3). They have shown that recombinant vectors expressing B7-1 are superior to unmodified vaccinia and fowlpox. Notably, they demonstrated that the combination of the 3 (B7-1, ICAM-1, and LFA-3) was superior to the vector modified with B7-1 alone.
Recombinant alphavirus and adenovirus are among other vector systems that show promise as vaccines. Recombinant adenoviral-based vaccines have been demonstrated to function well in a variety of settings and have been used in recent "prime" and "boost" strategies with plasmid DNA vaccines.2 In addition, a number of modifications of adenoviral vectors have been made to enhance entry into cells of interest, such as dendritic cells, or to deliver a gene with a desired immunologic activity.3-5
What is the optimal combination of costimulatory molecules and how should they be delivered? Options include the use of membrane-bound molecules that have direct effects on neighboring cells and serve to enhance the biologic activity of cells in vivo. Other alternatives include generating vectors that secrete a biologically active molecule that could target neighboring cells but also affect cells within the region. Tang and colleagues (Zhang et al6) previously reported construction of a recombinant adenoviral vector encoding a fusion protein composed of an amino-terminal tumor-associated antigen fragment fused to the CD40 ligand (CD40L). This vaccine was effective in overcoming anergy to TAA in experimental animals.
In this issue, Tang and colleagues extend their studies and report on the multistep process through which this adenoviral vector vaccine overcomes anergy to TAA. The authors attempt to dissect the role of these molecules and contribute to our understanding of how these modifications work. They show that subcutaneous injection of the Ad-sig-TAA/ecdCD40L vector resulted in the secretion of the TAA fused to the CD40L for at least 10 days. The absence of preexisting immune response to adenovirus makes it difficult to interpret how these findings will be translated to human studies. Also, secreted fusion molecules may elicit neutralizing antibodies, which may have untoward long-term effects.7 Nonetheless, this report by Tang and colleagues justifies continued investigation into recombinant vectors that can coexpress molecules on the cell surface or secrete them to optimize desired immune response.
References
- Hodge JW, Sabzevari H, Yafal AG, Gritz L, Lorenz MG, Schlom J. A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res. 1999;59: 5800-5807.[Abstract/Free Full Text]
- Meng WS, Butterfield LH, Ribas A, et al. alpha-Feto-protein-specific tumor immunity induced by plasmid prime-adenovirus boost genetic vaccination. Cancer Res. 2001;61: 8782-8786.[Abstract/Free Full Text]
- Belousova N, Korokhov N, Krendelshchikova V, et al. Genetically targeted adenovirus vector directed to CD40-expressing cells. J Virol. 2003;77: 11367-11377.[Abstract/Free Full Text]
- Worgall S, Busch A, Rivara M, et al. Modification to the capsid of the adenovirus vector that enhances dendritic cell infection and transgene-specific cellular immune responses. J Virol. 2004;78: 2572-2580.[Abstract/Free Full Text]
- Bukczynski J, Wen T, Ellefsen K, Gauldie J, Watts TH. Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses. Proc Natl Acad Sci U S A. 2004;101: 1291-1296.[Abstract/Free Full Text]
- Zhang L, Tang Y, Akbulut H, Zelterman D, Linton PJ, Deisseroth AB. An adenoviral vector cancer vaccine that delivers a tumor-associated antigen/CD40-ligand fusion protein to dendritic cells. Proc Natl Acad Sci U S A. 2003;100: 15101-15106.[Abstract/Free Full Text]
- Herzyk DJ. The immunogenicity of therapeutic cytokines. Curr Opin Mol Ther. 2003;5: 167-171.[Medline]
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Multistep process through which adenoviral vector vaccine overcomes anergy to tumor-associated antigens
- Yucheng Tang, Lixin Zhang, Jing Yuan, Hakan Akbulut, Jonathan Maynard, Phyllis-Jean Linton, and Albert Deisseroth
Blood 2004 104: 2704-2713.
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