Scientists have noted the ability of viruses to kill tumor cells for almost a century but have been unable to document the therapeutic use of these viruses in patients with cancer. Interest in this approach is growing, supported by advancing knowledge of viral biology, molecular genetics and tumor immunology. Oncolytic virus immunotherapy is a type of cancer treatment that uses viruses to replicate within cancer cells.
In this blog, we’ll briefly explore how viruses, specifically oncolytic viruses, are being used to treat cancer.
How Viruses Work… with Cancer Cells
All viruses share certain properties, including a genetic element and the ability to infect and replicate inside host cells under certain conditions. Viral infections can produce a variety of outcomes, depending on the pathogenic nature of the virus genetics, the ability of the virus to replicate or induce latency, and specific interactions between the virus and the host’s immune system.
Oncolytic viruses are a new class of immunotherapeutic agents that utilize viruses to target, infect and kill cancer cells. Oncolytic viruses have a dual mechanism action that selectively kills tumor cells and induces systemic anti-tumor immunity. The molecular and cellular mechanisms behind these actions are not fully understood but they are likely to rely on a combination of factors, including viral replication inside transformed cells, interaction with the antiviral elements of tumor cells, initiation of anti-tumor immunity, and the induction of primary cell death. Researchers have developed several native and genetically modified viruses to use as oncolytic agents and the U.S. Food and Drug Administration (FDA) is considering approval of the first oncolytic virus.
Certain viruses can enter cancer cells and replicate within them. While oncolytic viruses can enter normal cells or cancer cells, the abnormalities within cancer cells give oncolytic viruses a distinct advantage for viral replication. Specifically, cancer cells often demonstrate an abnormal stress response, cell signaling, and homeostasis. Furthermore, the normal antiviral machinery of the host cell, which would typically detect and clear viruses, may be abnormal in cancer cells. Protein kinase R (PKR) is critical to clearing intracellular viral infections, for example, and it may be completely absent in some cancer cells.
Oncolytic Viruses Impede Tumor Activity
Unlike standard virus-based vaccines, oncolytic viruses directly infect tumor cells and cause lysis in situ. As an added benefit, oncolytic viruses can also elicit danger signals that can serve as an anti-tumor immune response.
Oncolytic viruses may mediate tumor activity in two ways. First, selective replication within neoplastic cells can cause lysis within the tumor cell. Second, these viruses can induce systemic anti-tumor immunity to eliminate residual cancer cells. The nature and type of cancer cell, the characteristics of the individual virus, and the overall interaction between the virus, tumor and host immune system mediates the relative contribution of these two mechanisms.
Oncolytic Viruses in Advanced Clinical Trials
After a considerable amount of work to attenuate pathogenicity and enhance immunogenicity, research teams are proposing several viruses as vectors for use in oncolytic virus immunotherapy. Contenders entering early-phase clinical trials include Adenoviruses, Poxvirus, coxsackievirus, HSV-1, Measles virus, Poliovirus, Newcastle disease virus (NDV), and Reovirus.
Two oncolytic viruses, T-VEC and H101, have reached the regulatory review stage. H101 is a genetically modified Adenovirus. In 2005, China approved the use of H101 combined with chemotherapy as a treatment for nasopharyngeal carcinoma.
Talimogene laherparepvec (T-VEC) has undergone extensive clinical testing for use as a treatment for advanced melanoma. Oncology Nursing News reports FDA’s Oncologic Drugs Advisory Committee (ODAC) and Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) voted 22-1 to recommend T-VEC as a treatment for patients with this condition.
Challenges to the Development of Oncolytic Viruses
Researchers face many challenges in developing oncolytic virus as a new class of anti-cancer immunotherapies. There is a need for more practical trial designs and assessment criteria in addition to validated pharmacodynamic and pharmacokinetic assays. Biosafety is always a concern, particularly since oncolytic viruses are live viruses that proliferate upon clinical administration. Further investigation is needed to determine viral replication and clinical response, and clinical trials are essential for establishing safe and effective dosages. Drug developers must also manage non-traditional regulatory challenges and issues regarding commercialization and manufacturing.
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