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Background: T-SIGn (Tumor-Specific Immuno Gene Therapy) vectors are transgene-expressing variants of the blood-stable adenovirus enadenotucirev. Through a novel multimodal combination of immunostimulatory effects the vectors are designed to re-program ‘cold’ tumor microenvironments (TME) to allow functional anti-cancer immune responses. T-SIGn vectors selectively replicate in tumor cells, allowing IV delivery to be coupled with local transgene expression in the TME, thereby targeting all tumor lesions while limiting systemic exposure. NG-641 is a T-SIGn vector that expresses a fibroblast activation protein-directed bi-specific T-cell activator antibody to target cancer-associated fibroblasts (CAFs) and an immune-enhancer module (CXCL9/CXCL10/IFNα2) to recruit and activate immune cells. In an ongoing study (NCT04053283), NG-641 monotherapy has been successfully dose-escalated to 1 × 1012 viral particles (vp) on Day 1 and 3 × 1012 vp on Days 3 and 5; initial results from this study have shown a manageable tolerability profile and elevations in serum cytokines indicative of T-cell activation. Based on these promising initial data with NG-641 monotherapy, we designed a new study to assess NG-641 + nivolumab. Methods: NEBULA (NCT05043714) is an open-label, dose-escalating, phase 1a/b study of NG-641 + nivolumab. Eligible patients (pts) have advanced/metastatic epithelial tumors that have progressed after ≥1 line of systemic therapy and are incurable by local therapy. Pts eligible for phase 1a must have received prior PD-1/PD-L1 inhibition as part of any line of therapy; pts eligible for phase 1b must have primary resistance to PD-1/PD-L1 inhibition. During phase 1a, up to 30 pts will receive escalating doses of IV NG-641 (Bayesian Optimal Interval design) to a maximum dose of 1 × 1012 viral particles (vp) on Day 1 and 1 × 1013 vp on Days 3 and 5 (1 cycle). Pts will receive a fixed-dose of nivolumab (480 mg IV) on Day 15 and then every 4 weeks thereafter for up to 8 cycles. Phase 1b will further investigate the selected dose regimen in up to 3 tumor-specific cohorts (Cohorts A, B and C) using a Simon 2-stage design. Co-primary objectives are to characterize the safety and tolerability of NG-641 + nivolumab and to identify a recommended dose. Preliminary efficacy and immunogenicity are secondary endpoints. Pharmacodynamic outcomes will be assessed using tumor tissues and blood. Analyses of tumor tissue (serial biopsies at baseline and Day 15 of cycles 1-3 [cycles 1-2 only in Phase 1b]) will explore virus replication, transgene expression, immune/inflammatory responses and effects on CAFs by immunohistochemistry and gene expression analysis. Analyses of serial blood samples will explore cytokine production and changes in peripheral immune cell subsets. Enrollment to the first dose-escalation cohort is ongoing. Citation Format: Tom Lillie, Eileen Parkes, Christian Ottensmeier, David Krige, Behnaz Ravanfar, Vladimir Evilevitch, Matthew Thomas, Lee Rosen. A multicenter phase 1a/b study of NG-641, a tumor-selective transgene-expressing adenoviral vector, and nivolumab in patients with metastatic or advanced epithelial tumors (NEBULA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT214.

TPS2682 Background: Tumor-Specific Immuno Gene Therapy (T-SIGn) vectors are next-generation transgene-armed variants of the adenoviral vector enadenotucirev that selectively replicate in epithelial tumor cells. T-SIGn vectors are blood-stable, allowing IV delivery to be coupled with local transgene expression in the tumor microenvironment (TME), thereby targeting all lesions while limiting systemic exposure. The T-SIGn vector NG-641 encodes four immunostimulatory transgenes: fibroblast activation protein-directed bi-specific T-cell activator antibody to target cancer-associated fibroblasts (CAFs), IFNα2 to promote innate and adaptive immune responses, and CXCL9/10 to induce T-cell infiltration. Through this novel multimodal combination of immunostimulatory effects NG-641 is designed to re-program the TME to allow functional anti-cancer immune responses. In the ongoing STAR study (NCT04053283), NG-641 has been successfully dose-escalated to 1 × 1012 viral particles (vp) on Day 1 and 3 × 1012 vp on Days 3 and 5, with promising preliminary safety/tolerability and pharmacodynamic results. Based on these encouraging preliminary data with NG-641 monotherapy, we designed a new study to assess NG-641 + nivolumab. Methods: NEBULA (NCT05043714) is an open-label, dose-escalating, phase 1a/b study of NG-641 + nivolumab in patients (pts) with advanced/metastatic epithelial tumors that have progressed after ≥1 line of systemic therapy and are incurable by local therapy. Pts are eligible for phase 1a if they have received prior PD-1/PD-L1 inhibition as part of any line of therapy. During phase 1a, up to 30 pts will receive escalating doses of IV NG-641 to a maximum dose of 1 × 1012 viral particles (vp) on Day 1 and 1 × 1013 vp on Days 3 and 5 (1 cycle; Bayesian Optimal Interval design). Pts will receive a fixed-dose of nivolumab (480 mg IV) on Day 15 and then every 4 weeks thereafter for up to 8 cycles. In phase 1b, the recommended dose regimen will be further studied in patients with primary resistance to PD-1/PD-L1 inhibition; patients will be enrolled in up to 3 tumor-specific cohorts (Cohorts A-C; Simon 2-stage design). Co-primary objectives are to characterize the safety and tolerability of NG-641 + nivolumab and to identify a recommended dose. Preliminary efficacy and immunogenicity are secondary endpoints. Pharmacodynamic outcomes will also be assessed. Viral replication, transgene expression, immune/inflammatory responses and effects on CAFs by IHC and gene expression analysis will be analyzed using tumor tissue from serial biopsies (taken at baseline and Day 15 of cycles 1-3 [cycles 1-2 only in Phase 1b]). Serial blood samples will be analyzed to study cytokine production and changes in peripheral immune cell subsets. Enrollment to the first dose-escalation cohort is ongoing. Clinical trial information: NCT05043714.

2572 Background: Tumor-selective viruses, particularly those dosed systemically to deliver transgenes, are potentially powerful cancer therapies. However, acute cytokine reactions to viral particle (vp) infusion may affect vector tolerability [Small 2006], thereby limiting the maximum tolerated dose (MTD) and subsequent transgene delivery. T-SIGn vectors (e.g. NG-641 and NG-350A) are transgene-armed variants of the epithelial tumor-selective adenovirus enadenotucirev (EnAd). Acute serum cytokine increases post-dosing have been seen at the MTD of EnAd (“flat” dosing of 3 x 1012 vp on Days [D] 1, 3 and 5) [Machiels 2019]. Following supportive preclinical data [McElwaine-Johnn 2019], we explored if a LHH dosing regimen, in which a lower dose is given on D1 prior to two higher doses on D3 and 5, may improve vector safety/tolerability thereby allowing higher cumulative doses to be given. Methods: Data were pooled from three Phase 1 dose-escalation studies in advanced/metastatic epithelial cancer: SPICE (EnAd + pembrolizumab/nivolumab; NCT02636036), FORTITUDE (NG-350A ± pembrolizumab; NCT03852511) and STAR (NG-641; NCT04053283). Serum cytokines were measured using a 17-analyte Luminex assay. IL-6/MCP-1 data for D1, 3 and 5 (pre- and 6-10 hrs post-dose) were analyzed to examine acute cytokine changes. TNFα/IFNγ were examined due to their association with cytokine release syndrome (CRS). Samples analyzed from SPICE/FORTITUDE were taken before PD-1 inhibitor administration. Results: 84 patients (SPICE n=51; FORTITUDE n=18; STAR n=15) were included in these analyses; 79 had cytokine data. AEs and Gr≥3 AEs within 1 wk of first dose, and DLTs at any time, were less frequent with a LHH vs flat dosing regimen (Tbl). Importantly, a LHH dose of 1-6-6 (1 x 1012 vp on D1; 6 x 1012 vp on D3 and 5; greater than the previous flat MTD) was tolerated. Acute increases in TNFα/IFNγ were limited and no severe CRS was seen. Increases in IL-6/MCP-1 with 1 x 1011 or 1 x 1012 vp flat dosing were negligible, whereas acute increases in IL-6/MCP-1 were seen after the first dose of 3 x 1012 vp when given as a flat dose (negligible increases on D3/5). Notably, cytokine responses with 1-3-3 dosing (1 x 1012 vp on D1; 3 x 1012 vp on D3 and 5), including after the first 3 x 1012 vp dose on D3, were negligible. Cytokine responses after the first dose of 6 x 1012 vp in the 1-6-6 regimen were similar to those seen with the first dose of the flat 3 x 1012 vp regimen. Conclusions: LHH dosing appears to induce a desensitization mechanism allowing higher cumulative doses of T-SIGn vectors to be given without the associated acute reactions to viral infusions. This finding may have implications for optimizing safety-efficacy profiles of viral vectors in cancer. Clinical trial information: NCT02636036, NCT03852511 and NCT04053283. [Table: see text]