DDDR-48. An AAV-1 mediated dual-payload gene therapy for high grade glioma

Abstract BACKGROUND There have been few advances in glioblastoma treatment in recent decades. Treatments fail due to tumour heterogeneity (genetic, epigenetic, cell-state) and persistence of GBM stem-like cells (GSCs) within the tumour margin. SOX2 and SOX9 are consistently overexpressed in GSCs – an exploitable commonality across diverse tumour subtypes. Cell type-specific promoters are used in gene therapy to restrict therapeutic payload expression but often have suboptimal strength, selectivity, and size. RESULTS Focusing on the core SOX-driven transcriptional regulatory network in GSCs, we engineered synthetic super-enhancers (SSEs) with robust activity and exquisite cell state selectivity. TGX-007 is an AAV-1 mediated therapy delivering a combination of cytotoxic (HSVtk) and immune-modulatory (IL12) genetic payloads under the control of our SSE. We show that TGX-007 is curative in an aggressive immunocompetent mouse glioblastoma model, without off-target toxicities and with generation of immunological memory, preventing tumour formation on re-exposure. >85% of mice treated with TGX-007 were cured; all control mice died within 50 days. Treated mice were re-exposed to tumorigenic cells at 20 weeks and none developed tumours; all control mice developed tumours and died. A clear dose-response relationship was seen between TGX-007 concentration and cure rate in mice. AAV-SSE activity and selectivity was validated using primary human GBM tissue and normal cortex. CONCLUSIONS These findings provide the rationale for a first-in-human, phase I/II Bayesian optimal interval study to establish the safety and OBD of TGX-007 and to assess preliminary efficacy of TGX-007 in patients with newly-diagnosed GBM or with first radiological progression of previously treated GBM. TGX-007 will be administered with intra-operative MRI guidance via convection enhanced delivery. Patients will then receive 2 weeks valaciclovir (HSVtk substrate) prior to surgical debulking, then standard-of-care treatment. The OBD will be selected based on toxicity and tissue activity; signal of clinical efficacy will be assessed by overall survival.