Efficacy of coxsackievirus A21 against drug-resistant neoplastic B cells

Matthew Holmes; Gina B Scott; Samuel Heaton; Tyler Barr; Basem Askar; Louise M E Müller; Victoria A Jennings; Christy Ralph; Cathy Burton; Alan Melcher; Peter Hillmen; Christopher Parrish; Fiona Errington-Mais

doi:10.1016/j.omto.2023.03.002

Efficacy of coxsackievirus A21 against drug-resistant neoplastic B cells

Mol Ther Oncolytics. 2023 Mar 24:29:17-29. doi: 10.1016/j.omto.2023.03.002. eCollection 2023 Jun 15.

Authors

Affiliations

¹ Leeds Institute of Medical Research, University of Leeds, Beckett Street, Leeds LS9 7TF, UK.
² The Institute of Cancer Research, Division of Radiotherapy and Imaging, Chester Beatty Laboratories, London SW3 6JB, UK.
³ Haematological Malignancy Diagnostic Service, Leeds Teaching Hospitals, Beckett Street, Leeds LS9 7TF, UK.
⁴ St James's University Hospital, Leeds Teaching Hospital, Beckett Street, Leeds LS9 7TF, UK.

Abstract

Primary drug resistance and minimal residual disease are major challenges in the treatment of B cell neoplasms. Therefore, this study aimed to identify a novel treatment capable of eradicating malignant B cells and drug-resistant disease. Oncolytic viruses eradicate malignant cells by direct oncolysis and activation of anti-tumor immunity, have proven anti-cancer efficacy, and are safe and well tolerated in clinical use. Here, we demonstrate that the oncolytic virus coxsackievirus A21 can kill a range of B cell neoplasms, irrespective of an anti-viral interferon response. Moreover, CVA21 retained its capacity to kill drug-resistant B cell neoplasms, where drug resistance was induced by co-culture with tumor microenvironment support. In some cases, CVA21 efficacy was actually enhanced, in accordance with increased expression of the viral entry receptor ICAM-1. Importantly, the data confirmed preferential killing of malignant B cells and CVA21 dependence on oncogenic B cell signaling pathways. Significantly, CVA21 also activated natural killer (NK) cells to kill neoplastic B cells and drug-resistant B cells remained susceptible to NK cell-mediated lysis. Overall, these data reveal a dual mode of action of CVA21 against drug-resistant B cells and support the development of CVA21 for the treatment of B cell neoplasms.

Keywords: B cell neoplasm; Burkitt lymphoma; Chronic Lymphocytic Leukemia; Diffuse large B cell lymphoma; Non hodgkin lymphoma; coxsackievirus A21; drug resistance; oncolytic virus; tumor microenvironment.