Background NG-641 is a tumour-selective adenoviral vector that expresses a fibroblast activation protein-directed bi-specific T-cell activator antibody (FAP-TAc) and potent immune cell enhancers (CXCL9/CXCL10/IFNα). FAP-TAc targets killing of immunosuppressive cancer-associated fibroblasts, while immune enhancers recruit and activate immune cells (e.g. CD8+ T cells and dendritic cells). NG-641 is stable in the bloodstream and has low immunogenicity, allowing for IV delivery. We report first-in-human dose-escalation results for this novel immunotherapy.

Methods STAR (NCT04053283) is a Phase 1 study of NG-641 in patients with metastatic/advanced epithelial tumours and no standard treatments. The primary objective was safety and tolerability of IV NG-641 monotherapy (one cycle with single doses on Days 1, 3 and 5; five increasing dose levels). Preliminary anti-tumour activity was a secondary objective.

Results As of June 2022, 20 heavily pre-treated patients (median 60 years; 55% male) with metastatic/advanced epithelial tumours (35% colorectal; 15% pancreatic; 10% liver) received NG-641. DLTs of hypertension and dyspnoea occurred in one patient at Dose Level [DL] 2. The first patient at DL5 (1×10¹² vp on Day 1 and 1×10¹³ vp on Days 3 and 5) experienced a DLT of Grade 3 CRS following an innate response to viral particles. The NG-641 MTD was thus determined to be 6×10¹² vp as part of a “low-high-high” dosing regimen. Overall, the NG-641 safety profile was consistent with acute reactions to viral particles, with no evidence of transgene-related toxicity (table 1). Dose-dependent, specific and sustained increases in serum IL-12, IFNγ and IL-17a were detected from ~Wk2-12 (last measurement). Similar elevations did not occur with the unarmed parent vector, suggesting a transgene driven effect. No systemic FAP-TAc transgene protein was detected at any dose level indicating a lack of spill over from tumour into systemic circulation. Among evaluable patients, increases in tumour CD8+ T-cell infiltration were seen in 3/7 patients, including one patient with pancreatic cancer and one with colorectal cancer. No objective responses occurred but 2/3 patients at DL3 had stable disease (DL4 under assessment).

Conclusions NG-641 demonstrated manageable tolerability, with no evidence of systemic transgene-related toxicity. The MTD of NG-641 was 6×10¹² vp when given in a “low-high-high” dosing regimen. Consistent with the encoded immunostimulatory transgenes, NG-641 led to specific and sustained cytokine responses, without systemic spill over of transgene products from the tumour microenvironment. These results suggest that NG-641 drives local immunological tumour changes without systemic toxicity. A further trial (NEBULA, NCT05043714) examining NG-641 with nivolumab is ongoing.

Acknowledgements This study was funded by PsiOxus Therapeutics Limited. Medical writing support: Sandra Borkowska-Heurtaux, PhD, of PsiOxus Therapeutics Limited.

Trial Registration NCT number: NCT04053283

Ethics Approval This study was approved by

UT MD Anderson Cancer Center IRB (Protocol 2019-0636)

UCLA Institutional Review Board (IRB#21-000275)

University of Southern California Institutional Review Board (Proposal #HS-19-00696)

Ochsner Health System Institutional BioSafety Committee (Protocol 2019.02)

WIRB/Wcg IRB (Tracking number 20190830; Washington University in St. Louis; Moffitt – Advent Health)

Consent All patients provided informed consent before taking part in this study.