Pseudotyped lentiviral vectors: Ready for translation into targeted cancer gene therapy?

Abstract

Gene therapy holds great promise for curing cancer by editing the deleterious genes of tumor cells, but the lack of vector systems for efficient delivery of genetic material into specific tumor sites in vivo has limited its full therapeutic potential in cancer gene therapy. Over the past two decades, increasing studies have shown that lentiviral vectors (LVs) modified with different glycoproteins from a donating virus, a process referred to as pseudotyping, have altered tropism and display cell-type specificity in transduction, leading to selective tumor cell killing. This feature of LVs together with their ability to enable high efficient gene delivery in dividing and non-dividing mammalian cells in vivo make them to be attractive tools in future cancer gene therapy. This review is intended to summarize the status quo of some typical pseudotypings of LVs and their applications in basic anti-cancer studies across many malignancies. The opportunities of translating pseudotyped LVs into clinic use in cancer therapy have also been discussed.

Keywords: Cancer therapy; Clinical translation; Gene delivery; Lentiviral vector; Pseudotype.

Figure 1

Modifications of HIV-1 genome for developing a vector plasmid with improved safety. Various critical accessory and regulatory components within the HIV-1 genome are removed or substituted in order to construct a safe viral vector. LTR, long-terminal repeats; gag, group-specific antigen; pol, DNA polymerase; vif, viral infectivity factor; vpr, viral protein R; vpu, viral protein u; nef, negative regulator factor; env, viral envelope; RRE, rev response element; tat, transactivator of transcription; rev, transactivating protein; CMV, cytomegalovirus; RSV, respiratory syncytial virus.

Figure 2

The pseudotypings of LVs and their production. Packaging cells are transfected with a three-plasmid system consisting of a transgene vector, packaging vectors and an envelope vector, which encodes VSV-G, LCMV-G, MV-G or HCV-G, allowing production of different pseudotypes of LVs that have distinct tropisms. These assembled vector particles can be harvested from the supernatants and purified or concentrated further.

Figure 3

Applying pseudotyped LVs for cancer gene therapy. Four types of pseudotypes depicted here have been demonstrated to delivery transgenes, including suicide genes, CAR genes or other therapeutic genes into targeted cells, based on the specific interactions between pseudotyping glycoproteins and corresponding cellular receptors for vector entry. The suicide gene transduction of tumor cells leads to direct cell killing. While the transduction of immune cells, such as T cells, B cells or NK cells, can boost cancer immunotherapy, thus evoking tumoricidal activities. CAR, chimeric antigen receptor.