Nonreplicating Adenoviral Vectors: Improving Tropism and Delivery of Cancer Gene Therapy

Simple Summary The treatment of cancer has progressed greatly with the advent of immunotherapy and gene therapy, including the use of nonreplicating adenoviral vectors to deliver genes with antitumor activity for cancer gene therapy. Even so, the successful application of these vectors may benefit from modifications in their design, including their molecular structure, so that specificity for the target cell is increased and off-target effects are minimized. With such improvements, we may find new opportunities for systemic administration of adenoviral vectors as well as the delivery of strategic antigen targets of an antitumor immune response. We propose that the improvement of nonreplicating adenoviral vectors will allow them to continue to hold a key position in cancer gene therapy and immunotherapy. Recent preclinical and clinical studies have used viral vectors in gene therapy research, especially nonreplicating adenovirus encoding strategic therapeutic genes for cancer treatment. Adenoviruses were the first DNA viruses to go into therapeutic development, mainly due to well-known biological features: stability in vivo, ease of manufacture, and efficient gene delivery to dividing and nondividing cells. However, there are some limitations for gene therapy using adenoviral vectors, such as nonspecific transduction of normal cells and liver sequestration and neutralization by antibodies, especially when administered systemically. On the other hand, adenoviral vectors are amenable to strategies for the modification of their biological structures, including genetic manipulation of viral proteins, pseudotyping, and conjugation with polymers or biological membranes. Such modifications provide greater specificity to the target cell and better safety in systemic administration; thus, a reduction of antiviral host responses would favor the use of adenoviral vectors in cancer immunotherapy. In this review, we describe the structural and molecular features of nonreplicating adenoviral vectors, the current limitations to their use, and strategies to modify adenoviral tropism, highlighting the approaches that may allow for the systemic administration of gene therapy.