OR18

Lentivector onco-targeting for solid tumor gene therapy

J Rossi(1,2) L Sarmiento(1) R Sorrentino(1) E Manduchet(1,3) C Charbonnieras(1,3) S Fayet(1,3) J Cattiaux(3) S Kobold(2) A Bedel(1) F Moreau-Gaudry(1) V Guyonnet-Dupérat(3) S Dabernat(1)

1:Team Biotherapies Genetics and Oncology, BoRdeaux Institute of onCology (BRIC) U1312 University of Bordeaux, Bordeaux, 33000, France; 2:Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany; 3:Vectorology facility Vect'UB, TBMCore - CNRS UAR3427, INSERM US005, Univ. Bordeaux, F-33000 Bordeaux, France

Among the innovative therapeutic options in cancers refractory to current therapies, gene-based therapies show considerable promise. But first, cancer gene therapy needs efficient gene transfer into the tumors. Second, cancer gene therapy needs oncospecific transfer of the therapeutic genes, especially when bringing signals potentially harmful to healthy cells.

To obtain tumor-restricted oncotropism, we produced oncotropic lentiviral vector by engineering the E2 recognition glycoprotein of Sindbis virus (SINV-G) with a single-chain variable fragment (scFv), leaving intact the fusion E1 monomer. Unlike the scFv-engineered VSV-G which completely lost fusion activity, the scFv-SINV-E2 showed as efficient as the broad tropism VSV-G, but with exclusive specificity to cells expressing the targeted antigen. Moreover, with these envelope glycoproteins, the transduction efficiency was proportional to antigen expression by cancer cells, a crucial point when healthy cells display low expression of the targeted antigen. Intra-tumor injections of lentiviruses displaying scFv-SINV-E2 in mice bearing subcutaneous tumors produced transduction rates as efficient as lentiviruses displaying VSV-G. Importantly, while VSV-G lentivectors injected intravenously delivered the reporter gene at the injection site, in the liver, and in the bone marrow, scFv-SINV-E2 lentivectors reached only the tumors and its metastasis and no other detectable site, confirming the strong therapeutic anti-cancer value of lentivector onco-pseudotyping.

In conclusion, we confirmed that engineered oncotropic vectors target only the cancer cells, with high reproducibility and applicability for in vivo transfer of therapeutic genes. Considering the difficulty of reaching every tumor cell with toxic genes, this onco-specific targeting will be key for implementing intratumoral vulnerabilities.