Recombinant adenovirus-mediated cytotoxic gene therapy of lymphoproliferative disorders: is CAR important for the vector to ride?

The literature has seen an incredible booming of publications related to the use of recombinant adenoviruses as therapeutic tools for lymphoproliferative disorders over the last decade. Several approaches of adenovirus-mediated gene expression have been used to transfect cell lines that are derived from lymphoid tumors and would have otherwise been refractory to other transfection methods. The identification of high-affinity receptor for human adenoviruses serotype 2 and 5, the coxsackie-adenovirus receptor (CAR), has raised the question about its relevance for the efficacy of recombinant adenovirus-mediated gene therapy. We review published studies that have analyzed the use of recombinant adenovirus vectors expressing cytotoxic genes for gene therapy in lymphomas, chronic lymphocytic leukemia and multiple myeloma. For simplicity, we group all these diseases under the term lymphoproliferative disorders. We analyze the use of recombinant adenovirus-mediated cytotoxicity by assessing the importance of the biochemical and intrinsic signaling pathways interacting with the products of the exogenous viral-mediated expression. Ultimately, we discuss studies that have been finalized to by-pass the limitations of the biodistribution of CAR by modifying or targeting adenovirus to other membrane proteins in cells derived from lymphoproliferative disorders.