LCMV-GP-VSV-pseudotyped vectors and tumor-infiltrating virus-producing cells for the therapy of tumors
The invention relates to recombinant VSV viruses and viral vectors which produce a glycoprotein GP of the lymphocyte choriomeningitis virus (LCMV) instead of the G protein of the VSV, to virus producing cells which produce LCMV-GP-pseudotyped VSV virions, and to the use of said vectors and cells in the therapy of solid tumors, especially brain tumors.
1. A tumor-specific replication-competent vector construct comprising: a vesicular stomatitis virus (VSV) vector pseudotyped with glycoprotein GP of lymphocyte choriomeningitis virus (LCMV) (VSV-LCMV-GP pseudotype vector), wherein the vector comprises a gene coding for a glycoprotein GP of LCMV and the vector either lacks a functional gene coding for envelope protein G of VSV or the envelope protein G is replaced, wherein infection of cells with the replication-competent VSV-LCMV-GP pseudotype vector causes LCMV-GP to be encoded in the genome of a progeny viral particle and subsequently expressed on the surface of the progeny viral particle; and
wherein tropism of the progeny viral particle is independent of an additional tumor-targeting element or transgene in the VSV-LCMV-GP pseudotype vector and wherein the progeny viral particle exhibits tumor-specific replication competence.
2. The VSV-LCMV-GP pseudotype vector of claim 1 , wherein the envelope protein G is replaced by the glycoprotein GP of LCMV.
3. The VSV-LCMV-GP pseudotype vector of claim 1 , wherein the M protein of VSV comprises mutations that reduce cytopathogenicity of VSV.
4. The VSV-LCMV-GP pseudotype vector of claim 1 , wherein the vector further comprises at least one additional transgene encoding one or more of a suicide protein, an immunostimulatory protein, or a marker protein.
5. The VSV-LCMV-GP pseudotype vector of claim 4 , wherein the suicide protein is the thymidine kinase of the herpes simplex virus (HSV-TK), cytosine deaminase, FKBP-FAS, or FKBP-caspase9.
6. The VSV-LCMV-GP pseudotype vector of claim 4 , wherein the immunostimulatory protein is IL-2, IL-4, IL-12, neutralizing anti-TGFβ, or Flt3L.
7. The VSV-LCMV-GP pseudotype vector of claim 1 , wherein the LCMV is LCMV-WE, LCMV-WE-HPI or LCMV-WE-HPIopt.
8. The VSV-LCMV-GP pseudotype vector of claim 1 , wherein the progeny viral particle exhibits tumor-specific replication competence in one or more cells of a solid tumor.
9. The VSV-LCMV-GP pseudotype vector of claim 8 , wherein the one or more cells are from a glioblastoma.
10. The VSV-LCMV-GP pseudotype vector of claim 1 , wherein the glycoprotein GP of the VSV-LCMV-GP pseudotype vector is unmutated.
11. The VSV-LCMV-GP pseudotype vector of claim 1 , wherein the tumor-specific replication competence exhibited by the progeny viral particle is independent the glycoprotein GP of the VSV-LCMV-GP pseudotype vector or any modifications thereof.