Cancer gene therapy goes viral: viral vector platforms come of age

Abstract

Background: Since the advent of viral vector gene therapy in 1990s, cancer treatment with viral vectors promised to revolutionize the field of oncology. Notably, viral vectors offer a unique combination of efficient gene delivery and engagement of the immune system for anti-tumour response. Despite the early potential, viral vector-based cancer treatments are only recently making a big impact, most prominently as gene delivery devices in approved CAR-T cell therapies, cancer vaccines and targeted oncolytic therapeutics. To reach this broad spectrum of applications, a number of challenges have been overcome - from our understanding of cancer biology to vector design, manufacture and engineering. Here, we take an overview of viral vector usage in cancer therapy and discuss the latest advancements. We also consider production platforms that enable mainstream adoption of viral vectors for cancer gene therapy.

Conclusions: Viral vectors offer numerous opportunities in cancer therapy. Recent advances in vector production platforms open new avenues in safe and efficient viral therapeutic strategies, streamlining the transition from lab bench to bedside. As viral vectors come of age, they could become a standard tool in the cancer treatment arsenal.

Keywords: bioprocess platform; gene therapy; immunotherapy; oncolytic virus; viral vector.

Figure 1

Use of viral vectors in clinical trials to treat cancer. Overall, retrovirus viral family vectors are the most widespread. These include lenti- and gammaretroviruses, which are used in adoptive cell therapy. Other popular vectors for cancer treatment are adenovirus, poxvirus like vaccinia, herpes simplex virus (HSV) and adeno-associated virus (AAV). Measles virus, vesicular stomatitis virus (VSV) and poliovirus are some of the other vectors that are not explicitly depicted. Data on all open cancer trials are from Wiley Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide database (retrieved October 2021).

Figure 2

Overview of adenovirus vector design. (A) Schematic representation of adenovirus structure. Adenoviruses are non-enveloped 90 nm particles with pointing fibre rods. (B) Outline of wild type adenovirus genome, the first-generation adenovirus vector plasmid and helper-dependent adenoviral vector plasmid with the transgene expression cassette. The wild type genome highlights key early genes, while other genetic elements are omitted for clarity. The first-generation adenovirus vector particles are assembled in HEK 293 cell line by transgene vector plasmid transfection. Additionally, the helper-dependent vector assembly also requires infection with a helper virus. ITR = inverted terminal repeat; dsDNA = double-stranded DNA; pDNA = plasmid DNA.

Figure 3

Overview of AAV vector design. (A) Schematic representation of AAV structure. AAV virions are non-enveloped 25 nm icosahedral particles. (B) Outline of wild type AAV genome and AAV vector plasmid with the transgene expression cassette. AAV vector particles are assembled in adenoviral E1-expressing HEK 293 cell line, which is co-transfected with transgene AAV vector plasmid, a helper plasmid and a rep/cap plasmid. Alternatively, AAV vectors can be produced in insect cells, which are co-infected with ITR-flanked transgene and rep/cap recombinant baculoviruses. ITR = inverted terminal repeat; pDNA = plasmid DNA; ssDNA = single-stranded DNA

Figure 4

Overview of lentivirus vector design. (A) Schematic representation of lentivirus structure. Lentiviruses are 100 nm enveloped particles with exposed glycoprotein that defines the virus and vector tropism. (B) Outline of wild type lentivirus genome and lentivirus vector plasmid with the transgene expression cassette. Only key genetic elements are highlighted in the genome structure, rest are omitted for clarity. Lentivirus particles are assembled in mammalian cell culture by co-transfection of four plasmids: the transgene plasmid, gag/pol and rev packaging plasmids and VSV-G expression plasmid. pDNA = plasmid DNA; ssRNA = single-stranded RNA; LTR= long terminal repeat