1011P FORTITUDE phase I study of NG-350A, a novel tumour-selective adenoviral vector expressing an anti-CD40 agonist antibody: Monotherapy dose escalation results

Abstract

Multiple anti-CD40 antibodies (Abs) have been evaluated clinically, however they have shown limited efficacy as monotherapy. NG-350A is a novel transgene ‘armed’ tumour-selective adenoviral vector designed to re-engineer immunosuppressive tumours by expressing a fully human agonistic anti-CD40 Ab. As NG-350A selectively replicates in tumour cells, the anti-CD40 Ab is only expressed in the tumour microenvironment (TME), thereby limiting systemic exposure. Unlike many viral vectors, NG-350A is stable in blood allowing intravenous (IV) delivery to multiple tumor sites. In this phase I trial (NCT03852511) NG-350A was dose-escalated in patients (pts) with metastatic or advanced epithelial tumours in a 3+3 design. Here we present initial safety and pharmacodynamic data after completion of monotherapy dose-escalation. A total of 16 pts were treated at 3 IV dose levels, from 1x1011 virus particles (vp) on Days (D) 1, 3 and 5 to 1x1012vp on D1, followed by 6x1012vp on D3 and 5. Overall, NG-350A was well-tolerated, with no cases of Grade≥3 CRS nor evidence of raised liver enzymes. Dose-dependent specific increases in IL-12 and IFNγ were detected in serum of evaluable pts treated at higher dose levels, beginning at ∼Week2. In the majority of pts, IL-12 and IFNγ levels remained at ≥40pg/ml and 5x baseline levels at 7 weeks after dosing. NG-350A also led to the expansion of T-cell clones in blood with the majority of these being newly detected clones. These data suggest that NG-350A replicates in tumour cells and produces functional anti-CD40 within the TME, leading to higher and more sustained elevations in IL-12 and IFNγ than are typically observed with systemic anti-CD40 Abs. The elevations observed suggest innate immune cell stimulation and Th1-type T-cell activation, consistent with the mechanism of action of CD40 agonists. Together, these initial safety and biomarker data indicate that NG-350A may contribute to immunological re-engineering of the TME through localized production of anti-CD40, while avoiding the associated toxicity of systemic dosing, and support further clinical assessment of NG-350A in combination with anti-PD-1 Abs in FORTITUDE.