Conditionally replicative adenovirus as a therapy for malignant peripheral nerve sheath tumors

Julia A Nikrad; Robert T Galvin; Mackenzie M Sheehy; Ethan L Novacek; Kari L Jacobsen; Stanislas M A S Corbière; Pauline J Beckmann; Tyler A Jubenville; Masato Yamamoto; David A Largaespada

doi:10.1016/j.omton.2024.200783

Conditionally replicative adenovirus as a therapy for malignant peripheral nerve sheath tumors

Mol Ther Oncol. 2024 Feb 28;32(2):200783. doi: 10.1016/j.omton.2024.200783. eCollection 2024 Jun 20.

Affiliations

¹ Department of Pediatrics, Medical School, University of Minnesota, 420 Delaware Street SE, Mayo Mail Code 484, Minneapolis, MN 55455, USA.
² Department of Surgery, University of Minnesota, 516 Delaware Street SE, Minneapolis, MN 55455, USA.
³ Institute for Research in Immunology and Cancer, Université de Montréal, 2950 Chemin de Polytechnique Marcelle-Coutu Pavilion, Montréal, QC H3T1J4, Canada.
⁴ Masonic Cancer Center, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.

Abstract

Oncolytic adenoviruses (Ads) stand out as a promising strategy for the targeted infection and lysis of tumor cells, with well-established clinical utility across various malignancies. This study delves into the therapeutic potential of oncolytic Ads in the context of neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs). Specifically, we evaluate conditionally replicative adenoviruses (CRAds) driven by the cyclooxygenase 2 (COX2) promoter, as selective agents against MPNSTs, demonstrating their preferential targeting of MPNST cells compared with non-malignant Schwann cell control. COX2-driven CRAds, particularly those with modified fiber-knobs exhibit superior binding affinity toward MPNST cells and demonstrate efficient and preferential replication and lysis of MPNST cells, with minimal impact on non-malignant control cells. In vivo experiments involving intratumoral CRAd injections in immunocompromised mice with human MPNST xenografts significantly extend survival and reduce tumor growth rate compared with controls. Moreover, in immunocompetent mouse models with MPNST-like allografts, CRAd injections induce a robust infiltration of CD8+ T cells into the tumor microenvironment (TME), indicating the potential to promote a pro-inflammatory response. These findings underscore oncolytic Ads as promising, selective, and minimally toxic agents for MPNST therapy, warranting further exploration.

Keywords: MT: Regular Issue; conditionally replicative adenovirus (CRAd); cyclooxygenase 2 (COX2); malignant peripheral nerve sheath tumor (MPNST); neurofibromatosis type 1 (NF1); oncolytic adenovirus.