Immunization with Lentiviral Vector-Transduced Dendritic Cells Induces Strong and Long-Lasting T Cell Responses and Therapeutic Immunity

Abstract

Dendritic cell (DC) therapies are currently being evaluated for the treatment of cancer. The majority of ongoing clinical trials use DCs loaded with defined antigenic peptides or proteins, or tumor-derived products, such as lysates or apoptotic cells, as sources of Ag. Although several theoretical considerations suggest that DCs expressing transgenic protein Ags may be more effective immunogens than protein-loaded cells, methods for efficiently transfecting DCs are only now being developed. In this study we directly compare the immunogenicity of peptide/protein-pulsed DCs with lentiviral vector-transduced DCs, and their comparative efficacy in tumor immunotherapy. Maturing, bone marrow-derived DCs can be efficiently transduced with lentiviral vectors, and transduction does not affect DC maturation, plasticity, or Ag presentation function. Transduced DCs efficiently process and present both MHC class I- and II-restricted epitopes from the expressed transgenic Ag OVA. Compared with peptide- or protein-pulsed DCs, lentiviral vector-transduced DCs elicit stronger and longer-lasting T cell responses in vivo, as measured by both in vivo killing assays and intracellular production of IFN-γ by Ag-specific T cells. In the B16-OVA tumor therapy model, the growth of established tumors was significantly inhibited by a single immunization using lentiviral vector-transduced DCs, resulting in significantly longer survival of immunized animals. These results suggest that compared with Ag-pulsed DCs, vaccination with lentiviral vector-transduced DCs may achieve more potent antitumor immunity. These data support the further development of lentiviral vectors to transduce DCs with genes encoding Ags or immunomodulatory adjuvants to generate and control systemic immune responses.

Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics

“…104 Importantly, the resulting CTL response was protective against a subsequent challenge with a lethal dose of OVA-expressing B16 melanoma cells and slowed down the outgrowth of pre-existing tumors. 103,104 As these studies used exogenous and strong immunogenic antigens, they may overestimate the effects of lentivirally transduced DC against endogenous TAA.…”

“…Both human and murine lentivirally transduced DC were able to activate established CD4 + and CD8 + T-cell lines/ clones specific for epitopes derived from various relevant TAA, such as MAGE-3, 102 Melan-A/MART-1 92,96 and tyrosinase 93 in the human system and for the surrogate TAA ovalbumin (OVA) 88,103,104 as well as for TRP-2 97 in the murine system. These data show that DCs are capable of efficiently processing and presenting the lentivirally delivered transgene resulting in activation of established T cells.…”

Dendritic cell-directed lentivector vaccine induces antigen-specific immune responses against murine melanoma

“…Therefore, lentivectors have thus been proposed to be an ideal vector tool for vaccine delivery. 20,[24][25][26][27][28][29][30][31][32][33] Based on the study of Sindbis virus, a member of the Alphavirus genus and the Togaviride family, we have reported a mutant Sindbis virus glycoprotein, (SVGmu) which can specifically bind to DC-specific intracellular adhesion molecule (ICAM) 3 grabbing non-integrin (DC-SIGN, CD209). 34 DC-SIGN is a C-type lectin-like receptor and is expressed on DCs and macrophages.…”

Radiation to control transgene expression in tumors

“…While both virus-type vectors and nonviral vectors have been developed, the latter have not proved to be as effective as viral-based vectors in experimental systems and clinical applications. 59 Mammalian cells (e.g., fibroblasts, 60 dendritic cells 61,62 and blood endothelial cells 63 ) have also been considered as vehicles for delivery of anti-cancer therapeutics. However, the desired efficacy of cell-based strategies in general has not yet been reached, and specificity needs to be improved considerably.…”