Oncolytic Virus Therapy in Neuroblastoma: A Promising Avenue for High-Risk Patients

Abstract

Neuroblastoma (NB), a neuroendocrine cancer derived from the neural crest, is still the most common extracranial solid tumor in childhood. Low- and intermediate-risk patients have favorable outcomes, but high-risk NB still represents a major challenge for treatment. Even with improvement in multimodal treatments, such as chemotherapy, radiotherapy, and immunotherapy, the survival rate of high-risk NB remains unsatisfactory. In recent years, oncolytic virus (OV) therapy has appeared as a new and promising treatment modality. Genetically modified OVs selectively kill and lyse NB cells without harming normal tissues, bypassing the shortcomings of traditional therapies, including drug resistance and systemic toxicity. In addition, OVs can improve the effectiveness of other therapeutic agents when administered in combination therapy. Various clinical trials have shown promising results, with OVs such as Celyvir, Pexa-Vec (JX-594), and Seneca Valley Virus (NTX-010) showing safety and efficacy in pediatric patients. This review offers a thorough overview of OV therapy for NB, including preclinical studies, clinical trials, and prospects.

Introduction

Neuroblastoma (NB) is a sympathetic nervous system malignancy and the most prevalent extracranial solid cancer in children. Responsible for 8%–10% of all malignancies in childhood, NB mostly occurs in children under five years old. NB has extreme heterogeneity, and its clinical courses range from spontaneous remission in low-risk cases to aggressive disease progression in high-risk patients. Despite developments in therapeutic protocols, such as multimodal treatment with surgery, chemotherapy, radiotherapy, and immunotherapy, high-risk NB is still a significant therapeutic dilemma because of its high rate of recurrence and bad overall survival.

Of the newer therapeutic modalities, OV therapy has demonstrated great promise in treating high-risk NB. Oncolytic viruses are designed or naturally occurring viruses that selectively infect, propagate within, and kill cancer cells while leaving normal tissues intact. They cause not only direct oncolysis but also induce antitumor immune responses, rendering them a viable candidate for the treatment of aggressive cancers like NB. This review discusses mechanisms, present clinical uses, and promising areas of OV therapy in NB treatment.

Mechanisms of Oncolytic Virus Therapy

OV therapy exerts its antitumor effects through two primary mechanisms:

1. Direct Oncolysis:

   • OVs selectively infect NB cells due to their unique ability to exploit tumor-specific molecular pathways.

   • Upon infection, OVs replicate within cancer cells, leading to cell lysis and the release of viral progeny to infect neighboring malignant cells.

2. Immune System Activation:

   • Tumor cell lysis releases tumor-associated antigens (TAAs), triggering an immune response against NB cells.

   • Some OVs are engineered to express immune-stimulatory genes, enhancing T-cell activation and promoting systemic antitumor immunity.

   • OV therapy can reverse immune evasion mechanisms employed by NB, sensitizing tumors to immune checkpoint inhibitors.

Key Oncolytic Viruses in Neuroblastoma Therapy

Several OVs have been investigated for their potential in treating NB. Notable candidates include:

1. Celyvir (Mesenchymal Stem Cell-Carried Oncolytic Virus)

   • Calvin consists of an oncolytic adenovirus delivered via autologous mesenchymal stem cells (MSCs), which enhance tumor tropism and reduce immune clearance.

   • Clinical trials have demonstrated the safety and efficacy of Celyvir in pediatric NB patients, with some cases showing tumor regression and prolonged survival.

2. Pexa-Vec (JX-594)

   • Pexa-Vec is a genetically modified vaccinia virus engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF), enhancing immune responses.

   • Preclinical studies have shown robust antitumor activity against NB, and ongoing trials continue to evaluate its efficacy in pediatric patients.

3. Seneca Valley Virus (NTX-010)

   • NTX-010 is a naturally occurring picornavirus with selective tropism for neuroendocrine tumors, including NB.

   • Early-phase clinical trials have indicated its potential for inducing tumor regression in high-risk NB patients.

4. Herpes Simplex Virus (HSV-1) Derivatives

   • Genetically modified HSV-1 strains, such as G207 and HSV1716, selectively replicate in NB cells and trigger immune-mediated tumor destruction.

   • Promising results have been observed in preclinical models, warranting further clinical investigation.

5. Reovirus (Reolysin)

   • Reovirus preferentially infects cancer cells with an activated RAS signaling pathway, a feature present in many NB tumors.

   • Preclinical studies demonstrate strong synergy when combined with chemotherapy or immune checkpoint inhibitors.

Combination Therapy: Enhancing OV Efficacy

While OV therapy alone has demonstrated significant promise, combining OVs with existing treatment modalities enhances efficacy and mitigates potential limitations.

1. OVs + Chemotherapy

   • Chemotherapy-induced immunosuppression can be leveraged to allow OVs to persist longer in the bloodstream and tumor microenvironment.

   • Studies show that OVs can enhance chemosensitivity in NB cells, improving treatment response rates.

2. OVs + Radiotherapy

   • Radiotherapy induces tumor cell stress, increasing susceptibility to OV infection and replication.

   • Preclinical data suggest that OV-radiotherapy combinations yield superior tumor control compared to either modality alone.

3. OVs + Immunotherapy

   • Immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies) can enhance OV-mediated immune responses against NB.

   • OV therapy may also improve the efficacy of chimeric antigen receptor (CAR) T-cell therapy by modifying the tumor microenvironment.

Challenges and Future Directions

Despite the promise of OV therapy, several challenges must be addressed to optimize its clinical application in NB:

1. Immune System Clearance of OVs

   • Pre-existing antiviral immunity can limit OV persistence in circulation, necessitating strategies such as immune-evasive viral coatings or carrier cell delivery systems.

2. Tumor Heterogeneity

   • NB exhibits significant genetic and phenotypic heterogeneity, requiring personalized approaches for OV selection and combination therapies.

3. Optimizing Dosing and Delivery Methods

   • Determining the optimal OV dose and delivery route (intratumoral, intravenous, or via carrier cells) remains an area of active investigation.

4. Long-Term Safety Considerations

   • Although OV therapy has demonstrated a favorable safety profile, rigorous long-term follow-up studies are needed to assess potential risks, including unintended viral recombination.

Conclusion

Oncolytic virus therapy is a novel strategy in the management of high-risk neuroblastoma, providing tumor-specific cytotoxicity, immune stimulation, and possible synergy with standard treatments. Promising findings from preclinical and clinical trials highlight the potential of OVs like Celyvir, Pexa-Vec, and Seneca Valley Virus to enhance NB patient outcomes. Further research is needed to address current challenges, optimize therapeutic regimens, and provide long-term safety and efficacy. With continued progress in virotherapy, NB treatment strategies could soon see a revolutionary change towards more potent and less toxic therapies, ultimately enhancing survival and quality of life in infected children.