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Oncolytic viruses; Cancer therapy; Combination treatment; Immune response; Chemotherapy; Radiotherapy; Immunotherapy; Viral therapy; Cancer treatment resistance; Tumor targeting

Introduction

Cancer treatment has evolved significantly over the last few decades, moving from traditional approaches like surgery, chemotherapy, and radiotherapy to more targeted therapies and immunotherapies. Despite these advances, many cancers remain difficult to treat due to factors such as tumor heterogeneity, resistance to therapy, and the ability of cancer cells to evade immune surveillance. Among the innovative approaches gaining increasing attention is oncolytic virotherapy, which involves the use of genetically modified viruses that selectively infect and kill cancer cells while minimizing damage to healthy tissue [1].

Oncolytic viruses (OVs) can function independently or as part of combination therapies that include conventional cancer treatments such as chemotherapy, radiotherapy, and immunotherapy. This combinatory approach has shown the potential to enhance therapeutic outcomes by promoting synergistic effects. The rationale behind combining OVs with other therapies is to harness the tumor-specific targeting ability of the virus, while utilizing conventional treatments to prime the immune system, damage the tumor, or improve viral replication within the cancerous environment. This article will delve into the mechanisms by which oncolytic viruses work, their current applications in clinical settings, and the potential benefits and challenges of using them in combination with traditional cancer therapies. By examining current research and clinical trials, the article will evaluate how this treatment modality fits into the broader landscape of cancer therapy [2-5].

Description

Oncolytic viruses are naturally occurring or engineered viruses that can selectively infect and replicate within tumor cells, ultimately causing lysis (destruction) of these cells. Unlike most viruses, which infect both normal and cancerous cells, oncolytic viruses exploit the altered cellular machinery found in cancer cells, allowing for preferential infection and replication within tumor tissues [6].

Mechanisms of action

Oncolytic viruses induce tumor cell death through several mechanisms, which can be grouped into direct viral oncolysis and indirect immune-mediated effects. These mechanisms contribute to the unique ability of OVs to target cancer cells with minimal harm to surrounding healthy tissue. the oncolytic virus enters the tumor cell, it replicates rapidly and causes lysis, releasing new viral particles that infect neighboring cells. This process destroys tumor cells from within, reducing the overall size of the tumor. As the virus infects and lyses tumor cells, it releases tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs), which act as signals that activate the immune system. These immune signals can stimulate both the innate and adaptive immune response, promoting an anti-tumor immune reaction [7].

Oncolytic viruses can also help "re-educate" the immune system to recognize and target cancer cells, particularly in tumors that are immunosuppressive or have evolved mechanisms to evade immune surveillance. Various viruses have been explored for their oncolytic potential. They can be naturally occurring, genetically modified, or engineered for enhanced specificity and efficacy. Commonly used in oncolytic virotherapy, adenoviruses can infect and replicate in rapidly dividing tumor cells. Modified adenoviruses can be engineered to carry therapeutic genes that boost the anti-tumor immune response or make the virus more selective for cancer cells.

HSV has been genetically engineered to selectively infect tumor cells, replicate, and cause tumor cell destruction. Talimogene laherparepvec (T-VEC) is an FDA-approved oncolytic virus based on HSV, which has demonstrated effectiveness in treating melanoma [8].

The vaccinia virus has been used in oncolytic therapy, particularly due to its ability to infect and replicate within tumor cells while eliciting strong immune responses. This virus is often genetically engineered to enhance its selectivity and reduce the potential for harm to normal cells. Reoviruses selectively replicate in cells with activated Ras signaling pathways, which are common in cancerous cells. This selectivity makes them a promising candidate for oncolytic virotherapy. These viruses are also being investigated for their oncolytic potential, particularly in specific types of cancers such as glioblastomas and sarcomas [9,10].

Discussion

Oncolytic virotherapy alone has demonstrated encouraging results in preclinical models and early clinical trials, but its full therapeutic potential can be realized when combined with other established cancer therapies. Synergy between OVs and traditional treatments can be achieved in several ways. Chemotherapy remains a cornerstone of cancer treatment, especially for solid tumors and aggressive cancers. However, chemotherapy often has a limited ability to target only cancer cells, damaging healthy tissues in the process. Combining chemotherapy with oncolytic viruses can improve the efficacy of both approaches. Chemotherapy drugs can weaken the tumor's defenses, making cancer cells more vulnerable to viral infection and replication. Certain chemotherapy agents, especially those that act by inducing DNA damage or cell cycle arrest (e.g., cisplatin), can make tumor cells more susceptible to infection by oncolytic viruses. Additionally, chemotherapy can help reduce the size of the tumor, creating a more favorable environment for virus replication.

Chemotherapy may alter the tumor microenvironment by reducing intratumoral pressure or modifying blood vessel structure, which facilitates better viral delivery and penetration. Radiotherapy and oncolytic virus therapy share several similarities in their mechanisms, such as inducing cell damage and immune activation. When combined, these modalities can enhance each other's effects. Radiotherapy can prime the immune system by causing immunogenic cell death, and when combined with oncolytic viruses, it can improve viral replication in the tumor. Radiotherapy can increase the expression of viral receptors on tumor cells, facilitating the virus’s ability to infect and lyse the tumor more effectively. The combination of radiation and viral infection can also result in a more robust immune response against the tumor. Tumor cells killed by radiotherapy may release tumor antigens that act as a potent "feed" for the immune system, further enhancing the effects of oncolytic virotherapy.

Immunotherapy, especially immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1, anti-CTLA-4), has revolutionized the treatment of cancers, particularly for tumors like melanoma and non-small cell lung cancer. However, the response to immunotherapy can be limited, as many tumors have mechanisms to evade immune recognition. Oncolytic viruses have the ability to directly stimulate the immune system. By inducing an immune response to the tumor, they may increase the effectiveness of immune checkpoint inhibitors by "priming" the immune system to recognize and target cancer cells more efficiently. The combination of oncolytic viruses and checkpoint inhibitors has shown promise in overcoming immune tolerance in tumors that express PD-1/PD-L1, enhancing T-cell-mediated anti-tumor immunity.

Despite the promising potential of combining oncolytic viruses with other cancer treatments, several challenges remain. Tumors are genetically diverse, and different regions of the tumor may respond differently to viral infection or therapeutic agents. Ensuring uniform viral distribution and effectiveness remains a hurdle. The immune system may recognize the virus itself as a foreign pathogen, leading to the clearance of the virus before it can achieve therapeutic efficacy. Producing oncolytic viruses on a large scale is challenging. The delivery of these viruses to deep tumor regions and overcoming barriers like blood-brain barrier in certain cancers (e.g., gliomas) remain key issues.

Conclusion

Oncolytic viruses represent an exciting and innovative approach to cancer treatment, especially when used in combination with traditional therapies such as chemotherapy, radiotherapy, and immunotherapy. The ability of OVs to target tumor cells directly while stimulating the immune system provides a powerful tool for enhancing treatment efficacy and overcoming cancer resistance mechanisms. The combination of oncolytic virotherapy with other therapeutic modalities offers several potential advantages, such as improving viral replication within the tumor, boosting immune responses, and facilitating better tumor targeting. However, challenges such as tumor heterogeneity, immune responses against the virus, and efficient viral delivery must be addressed to fully realize the potential of this treatment strategy. As ongoing clinical trials continue to evaluate the safety and efficacy of oncolytic viruses in combination therapy, the future of this innovative approach appears promising. By leveraging the strengths of multiple treatment modalities, oncolytic viruses may play a significant role in personalized cancer therapy, offering a new frontier for patients with otherwise hard-to-treat cancers.

Acknowledgement

None

Conflict of Interest

None

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