25O - Phase I tolerability, persistence and pharmacodynamic (PD) profile of IV-administered next-generation adenoviral vectors supports clinical expansion in solid cancers

Background

Safe and effective IV administration (admin) of therapeutic viral vectors requires evasion of rapid viral clearance. Vectors must infect, propagate and, for armed vectors, express transgenes selectively within tumors. T-SIGn vectors have been designed to achieve these aims and alter the tumor microenvironment to induce durable antitumor immunity.

Methods

The unarmed tumour-selective chimeric group B adenovirus enadenotucirev (EnAd) was evaluated in phase 1 studies in advanced/metastatic epithelial tumors and in locally advanced rectal cancer (LARC). In preclinical studies of biological immune activators, CD40 was admin intratumorally in one tumor to simulate local immune activation anti-CD40 in bilateral B16 tumor-bearing mice. Transgene-armed T-SIGn vectors were then evaluated in phase 1 studies as monotherapy or with checkpoint inhibitors (CPIs) in epithelial tumors.

Results

EnAd has been dosed IV in 150 pts, with a well-tolerated dose regimen established (1 × 10¹² vp on D1 and 6 × 10¹² vp on D3 & 5 of a 28-day cycle). Chills and pyrexia were the most common TEAEs. Dose-dependent PK profiles showed sustained viral persistence after IV admin, with vector DNA found in post-treatment tumour samples. In a phase 1 study in LARC, EnAd plus chemoradiation led to high CR rates (42%; 5/12 pts) and a dose-dependent Neoadjuvant Rectal Score. Preclinical studies show that IT treatment with a CD40 agonist is sufficient to induce the expression of CD80, CD86, and IFN-gamma selectively within tumors. T-SIGn vector admin in n=89 pts has shown no evidence of transgene-related toxicity. Encouraging transgene mRNA and PD data has been identified for NG-350A, an anti-CD40 agonist expressing vector.

Conclusions

The sustained detection of vector DNA and persistence within tumors suggests next-generation T-SIGn vectors can be successfully administered IV. Preclinical studies support further clinical testing of targeted delivery of a CD40 agonist mAb with NG-350A to build on the intriguing results in the LARC pilot study and in disease-specific expansion cohorts in combination with CPIs.

Clinical trial identification

NCT03916510; NCT03852511.

Editorial acknowledgement

Legal entity responsible for the study

University of Oxford; Akamis Bio.

Funding

Funded in part by UCLH NIHR BRC; Akamis Bio.

Disclosure

D. Khalil, A. Naing: Financial Interests, Personal, Principal Investigator: Akamis Bio. A. Stacey, R.R. Ji: Financial Interests, Personal, Full or part-time Employment: Akamis Bio. M. Thomas: Financial Interests, Personal, Invited Speaker: Akamis Bio. O. Rosen: Financial Interests, Personal, Full or part-time Employment, Ownership: Akamis Bio. All other authors have declared no conflicts of interest.