Faculty, Staff and Student Publications
Publication Date
10-15-2024
Journal
The Journal for ImmunoTherapy of Cancer
DOI
10.1136/jitc-2024-010016
PMID
39414325
PMCID
PMC11481156
PubMedCentral® Posted Date
10-15-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Tumor-selective oncolytic viral vectors are promising anticancer therapeutics; however, challenges with dosing and potency in advanced/metastatic cancers have limited efficacy and usage. NG-350A is a next-generation blood-stable adenoviral vector engineered to express an agonist anti-cluster of differentiation (CD)40 antibody without affecting tumor-selectivity and oncolytic potency.
Methods: Intravenous and intratumoral (IT) administration of NG-350A was assessed in a phase Ia/Ib study in patients with metastatic/advanced epithelial tumors (NCT03852511). Dose-escalation was performed separately for intravenous (four dose levels available, each with infusions on Days 1, 3 and 5 of a 57-day treatment period) and IT (single injection on D1 only or injections on Days 1, 8, 15 and 22) administration. The primary objective was safety and tolerability; secondary objectives included determining a recommended dose, pharmacokinetics, and immunogenicity.
Results: In total, 25 heavily pretreated patients received NG-350A (16 with intravenous and 9 with IT administration). Intravenous and IT dosing were both well tolerated, with no evidence of transgene-related or off-target viral toxicity. Intravenous and IT dosing resulted in dose-dependent increases in systemic NG-350A Cmax. Despite both routes of administration inducing anti-virus antibodies, sustained persistence of NG-350A in blood samples was observed up to 7 weeks after the last dose, particularly with higher intravenous dose levels. Delivery of NG-350A to tumors was demonstrated in biopsy samples following both routes of administration; a dose-dependent pattern was seen with intravenous infusion, with four patients remaining positive for vector DNA in biopsies at Day 57. Transgene messenger RNA from replicating NG-350A was detected in 5/12 patients with intravenous treatment and 1/9 patients with IT injection, and sustained increases in inflammatory cytokines were observed following dosing, particularly with higher intravenous dose levels.
Conclusions: This phase 1a study provided initial proof-of-mechanism for NG-350A, with strong evidence of tumor delivery, viral replication and transgene expression-particularly after intravenous dosing. The lack of transgene-related or off-target viral toxicity was consistent with the highly selective delivery and replication of NG-350A, even after systemic delivery. The efficacy of intravenous-dosed NG-350A will now be evaluated in combination with pembrolizumab (NCT05165433), as well as with chemoradiotherapy (NCT06459869).
Keywords
Humans, Female, Male, Middle Aged, Tumor Microenvironment, Aged, Adult, Genetic Vectors, Neoplasms, Oncolytic Virotherapy, Treatment Outcome, Adenoviridae, Oncolytic virus, Immunotherapy, Pharmacokinetics - PK, Pharmacodynamics - PD, Solid tumor
Published Open-Access
yes
Recommended Citation
Naing, Aung; Khalil, Danny; Rosen, Oliver; et al., "First-in-Human Clinical Outcomes With NG-350A, an Anti-CD40 Expressing Tumor-Selective Vector Designed To Remodel Immunosuppressive Tumor Microenvironments" (2024). Faculty, Staff and Student Publications. 4873.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4873
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons
Comments
Trial registration number: NCT05165433, NCT06459869.