Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics

Therapeutic anti-cancer vaccines are required to reprogram a tolerized immune system. This is a major challenge for vaccine design and merits the development of novel immunisation protocols such as direct injection of lentiviral vectors for in vivo transduction of antigen-presenting cells, in particular dendritic cells (DC).
We demonstrated that self-inactivating lentiviral vectors containing the triple helix sequence are higly efficient in transduction of ex vivo generated human and mouse DC. Since, these vectors don't encode viral proteins, they don't hamper DC function and direct the immune response to only the transgene. We showed that ex vivo generated DC transduced with tumor-associated antigen (TAA) encoding lentiviruses induced strong cytotoxic T lymphocyte (CTL) responses both in vitro (MAGE-A3) and in vivo (ovalbumin) and that these DC are more potent than mRNA electroporated DC, which are currently evaluated in the clinic. Moreover, we demonstrated that direct administration of lentiviral vectors was even superior to ex vivo modified DC. The potency of the lentiviral vectors can be explained by their capacity to activate DC, through several pathogen recognition receptors, such as protein kinase R and toll-like receptors. Finally, we delivered the first proof-of-principle for directed lentiviral infection of target cells, i.e. tumor cells modified to express hen egg lysozyme, using lentiviruses containing an ecotropic envelope and membrane bound anti-hen egg lysozyme nanobodies, further optimizing the safety of lentivirus-based vaccines.
In conclusion, the presented data warrant further development of lentivirus-based vaccines for clinical application, with the purpose of targeting TAA, with or without immunomodulators, specifically to DC.