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

Abstract

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.

Keywords: cancer; gene therapy; nonreplicating adenovirus vector; routes of delivery; virus coated with cancer cell membrane.

Figure 1

Improvements in vector delivery to and targeting of cancer cells. (a) Several approaches can be used to modify viral attachment and entry, such as inhibiting the binding to natural receptors (detargeting) and creating tropism for neoplasms and their metastatic foci (retargeting). (b) An alternative to CAR-mediated viral attachment is modifying the fiber (for example, incorporation of the RGD sequence into the knob AB-loop motif). (c) Ad structure permits retargeting through the incorporation of synthetic molecules and antibody fragments within the virus capsid. (d) Both biological (e.g., cell membrane, liposome) and chemical (e.g., gold, silver, PEG) approaches may be used to coat the virus and improved delivery, especially for the systemic route. PEG: polyethylene glycol. Created with BioRender.com.

Figure 2

Strategy used to improve the specificity of adenoviral vectors. An adenovirus coated with a cancer cell membrane has some advantages, such as the presence of TSA and TAA, which aids the anti-tumor immune response. Additionally, the membrane can be engineered to present specific molecules/receptors, improving the power of interaction with the tumor. Moreover, the viral coating can offer several benefits, including suppression of liver toxicity, increase of specific infectivity to cancer cells, preferential antitumor (not antiviral) immune response, and escape from pre-existing neutralizing antibodies in both routes of delivery (intratumoral and systemic). Systemic administration using virus coated with membranes could offer a highly desirable outcome: targeting metastatic foci. TAA: tumor-associated antigens; TSA: tumor-specific antigens. Created with BioRender.com.