Gene delivery for immunoengineering

Abstract

A growing number of gene delivery strategies are being employed for immunoengineering in applications ranging from infectious disease prevention to cancer therapy. Viral vectors tend to have high gene transfer capability but may be hampered by complications related to their intrinsic immunogenicity. Non-viral methods of gene delivery, including polymeric, lipid-based, and inorganic nanoparticles as well as physical delivery techniques, have also been widely investigated. By using either ex vivo engineering of immune cells that are subsequently adoptively transferred or in vivo transfection of cells for in situ genetic programming, researchers have developed different approaches to precisely modulate immune responses. In addition to expressing a gene of interest through intracellular delivery of plasmid DNA and mRNA, researchers are also delivering oligonucleotides to knock down gene expression and immunostimulatory nucleic acids to tune immune activity. Many of these biotechnologies are now in clinical trials and have high potential to impact medicine.

Figure 1

Broad gene delivery strategies for cancer immunotherapy. Gene delivery can be accomplished using viral, lipid-based, or polymeric vectors, or a combination of various materials. These can be used to genetically engineer immune cells ex vivo for adoptive transfer, or they can modify tumor cells or immune cells directly in vivo to promote immune activation against the tumor. Some examples of gene delivery methods that can be used for tumor immunotherapy are shown here.

Figure 2

Strategies for improving the translatability of viral gene delivery. Viruses are effective gene delivery agents but must contend with safety challenges as well as their intrinsic immunogenicity. Several methods have been devised to overcome this, including coating viruses with polymers, blocking neutralization sites using polypeptides, and physically encapsulating the viruses to isolate them from immune cells. Reprinted with permission from Rajagopal et al., ‘Polymer-coated viral vectors: hybrid nanosystems for gene delivery’, J Gene Med 20(4):e3011, Copyright 2018, John Wiley and Sons [8^•].

Figure 3

Hybrid lipid-polymer materials can be used for pDNA delivery for tumor immunotherapy. The cationic polymer protamine was used to condense pDNA for PD-L1 trap, then coated with PEGylated lipids for stability and targeting (LPD) (a). These LPDs were injected into tumor-bearing mice along with systemic oxaliplatin (OxP) therapy (b), and the combination of OxP and PD-L1 trap expression significantly inhibited tumor growth (c and d). Adapted from Song et al., ‘Synergistic and low adverse effect cancer immunotherapy by immunogenic chemotherapy and locally expressed PD-L1 trap’, Nat Comm 9:2237, Copyright 2018, Springer Nature [32].