Demonstration Of Anti-Tumor Immunity Via Intratumoral Regulated Platform Ad-Rts-Hil-12 In Advanced Breast Cancer And Recurrent Glioblastoma Patients.

3038 Background: Ad-RTS-hIL-12 (Ad) is a novel gene therapy candidate expressing IL-12 under the control of an orally administered activator ligand, veledimex (V), through a proprietary RheoSwitch Therapeutic System (RTS) gene switch. This platform reduces systemic toxicity and stimulates anti-cancer T cell immune response. Methods: Two open label trials evaluated the tolerability of local inducible IL-12 expression in heavily pretreated patients with metastatic breast cancer (mBC) or recurrent glioblastoma (rGBM). Ad was administered as a single intratumoral injection with V 80 mg PO Qdx7 in mBC and 10-40 mg Qdx15 PO in rGBM. Results: We observed local expression of IL-12 and downstream IFNg demonstrating biological activity with a mean increase in tumor cytotoxic T cells (CD3+CD8+) baseline: 0.4 ± 0.2 to biopsy:1.9±0.8% cells with a mean reduction in Treg (CD4+FOXP3+) baseline: 0.8 ± 0.4 to biopsy: 0.6±0.3% cells. Sustained increases in tumor IFNg were documented in both mBC (by biopsy at Day 42 post injection) and rGBM (biopsy range:130 - 175 days post injection) while tumor IL-12 returned to baseline and systemic levels of IFNg and IL-12 were undetectable. In mBC, injected and non-injected lesions (abscopal effect) showed a reduction in lesion diameter. In the mBC study, 9 iRECIST evaluable subjects showed PR/stable disease in 5 subjects, for a disease control rate of 44% at Week 6 and 22% at Week 12. In the ongoing rGBM study we observe a mOS of 12.5 months with 5 of 15 subjects alive in the 20 mg V cohort with survival follow up ongoing. Across studies, the adverse event profile of Ad+ V, was predictable, controllable, and fully reversible upon stopping V including a dose response to frequency and severity of cytokine release syndrome. Conclusions: Local regulated controlled IL-12 expression using the Ad + V platform in advanced mBC and rGBM patients is promising, eliciting sustained increases in cytotoxic T cells, reduces Treg, including in non-injected lesions (abscopal effect) turning cold tumors hot, with a good safety profile. This platform warrants further evaluation in multiple tumor types in monotherapy and in combination with immune checkpoint inhibitors. Clinical trial information: NCT02026271; NCT02423902.