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Efficacy of coxsackievirus A21 against drug-resistant neoplastic B cells
Matthew Holmes1, Gina B Scott1, Samuel Heaton1
1Leeds Institute of Medical Research, University of Leeds, 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.
Insights
Coxsackievirus A21 (CVA21) effectively eliminates B cell neoplasms, including drug-resistant types. This oncolytic virus shows dual action, directly killing cancer cells and activating immune responses for enhanced treatment of B cell malignancies.
Area of Science:
- Oncolytic virotherapy
- Immunology
- Hematologic oncology
Background:
- Primary drug resistance and minimal residual disease present significant challenges in treating B cell neoplasms.
- Current treatment strategies require novel approaches to eradicate both malignant B cells and resistant disease.
Purpose of the Study:
- To investigate the potential of the oncolytic virus Coxsackievirus A21 (CVA21) as a novel therapeutic agent for B cell neoplasms.
- To assess CVA21's efficacy against drug-resistant B cell neoplasms and understand its mechanism of action.
Main Methods:
- Utilized CVA21 to treat various B cell neoplasms in vitro.
- Assessed CVA21 efficacy in the presence of anti-viral interferon response and tumor microenvironment-induced drug resistance.
- Investigated CVA21's dependence on oncogenic B cell signaling pathways.
- Evaluated CVA21's impact on natural killer (NK) cell activation and their role in targeting neoplastic B cells.
Main Results:
- CVA21 demonstrated efficacy in killing a broad spectrum of B cell neoplasms, independent of interferon response.
- CVA21 effectively eradicated drug-resistant B cell neoplasms, with efficacy sometimes enhanced by increased ICAM-1 expression.
- CVA21 exhibited preferential killing of malignant B cells and demonstrated dependence on oncogenic B cell signaling.
- CVA21 activated NK cells, which contributed to the lysis of both neoplastic and drug-resistant B cells.
Conclusions:
- CVA21 exhibits a dual mechanism of action against drug-resistant B cell neoplasms, involving direct oncolysis and immune activation.
- These findings support the further development of CVA21 as a therapeutic strategy for B cell malignancies, addressing challenges of drug resistance and minimal residual disease.
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