594 BT-001, an oncolytic vaccinia virus armed with a Treg-depleting human recombinant anti-CTLA4 antibody and GM-CSF to target the tumor microenvironment

Abstract

Background Checkpoint inhibitor antibodies have improved survival in a variety of cancers, however, a great unmet need remains since only a small fraction of patients responds. Reasons for lack of efficacy are believed to include lack of tumor infiltrating immune cells, a notion supported by improved efficacy observed following combined checkpoint blockade with tumor oncolytic virotherapy which promotes intratumoral T cell infiltration. Oncolytic vaccinia viruses (oVV) also allow genetic encoding of transgenes. This is of special interest for therapeutic proteins exhibiting toxicological limitation or pharmacokinetic issues. Here, BioInvent and Transgene present a potentially safe and more efficacious strategy to combine checkpoint inhibition in the context of oncolytic virotherapy. Methods Using the F.I.R.S.T™ discovery platform we have isolated a human recombinant Treg-depleting antibody that has been vectorized alongside GM-CSF into the Invir.IO® oVV. This product named BT-001 consists of a Copenhagen double deleted vaccinia virus encoding the human CTLA4-specific antibody 4-E03 IgG1, which shows improved Treg-depletion compared with ipilimumab in a human PBMC-based NOG/SCID-transfer model. BT-001 also encodes GM-CSF, the cytokine expressed in clinically approved products. A surrogate murine mAb was vectorized into the same oVV (mBT-1) allowing for functional and mechanistic in vivo studies. Results Our studies demonstrate that 4-E03 and GM-CSF were expressed as functional…