Systems modeling helps optimize safety and efficacy for oncolytic viruses

The ability of viruses to insert their genome into a host cell is leveraged in modern molecular biology. For example, recombinant viral vectors can manipulate the genes of a cell or organism.

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Non-cancerous cells and a competent immune system can arrest/eliminate a viral infection. By contrast, cancer cells often develop mutations that enable them to evade immune surveillance. However, such mutations also make them vulnerable to viral infections [4]. Modern research and development of oncolytic viruses is focused on

1. creating “attenuated” recombinant viruses that can shrink tumors
2. but have limited ability to infect healthy tissue
3. and don’t cause undesirable side effects or toxicity.

There are two key mechanisms of action oncolytic viruses take. Most modern virotherapies utilize recombinant DNA technologies to attenuate a wild-type virus. This engineered virus preferentially infects cancer cells while having a limited ability to infect healthy cells. Additionally, recombinant oncolytic viruses can “reprogram” cancer cells to change their microenvironment to drive cancer cell killing.

As a vector for gene manipulation, an oncolytic virus could use several possible strategies to reprogram the tumor microenvironment. For example, an oncolytic virus could prevent cancerous cells from expressing proteins that enable immune system evasion. Alternatively, it could make infected cells express proteins that recruit immune cells to the tumor.

Certain challenges are unique to the development of oncolytic viruses. One challenge with different oncolytic viruses is that they can have species-specific permissivity. A virus can have a different ability to infect and replicate in mouse versus human cells, for example. Therefore, it becomes difficult to translate preclinical doses to human applications.

Certara experts use modeling to bridge species differences and make human predictions. This approach can answer questions around toxicity and/or efficacy.

Another consideration is that oncolytic viruses are live, and upon clinical administration, will proliferate within the body, causing variable effective doses. Currently, there is not enough publicly available data to fully understand the relationship between viral replication and clinical outcomes. Understanding this relationship will be essential in establishing safe and effective doses. [5]

For small molecule drugs or monoclonal antibodies, we can correlate plasma drug measurements (pharmacokinetics; PK) to the efficacy/safety effects without understanding their mechanism of action. However, it’s difficult to relate the PK of the virus or other gene therapy vectors to efficacy/safety.

Understanding a viral therapy’s mechanism of action requires characterizing how cells take up genetic material and translate it into a protein. Mechanistic modeling can capture these subtleties because it models each step explicitly and uses species-specific information.

Unlike most drugs, the body doesn’t metabolize oncolytic viruses. Potential host’s antiviral immune responses include disabling the virus via circulating neutralizing antibodies or haemaggluttinin binding. In some cases, viruses evade immune detection.

Further research on how cancer patients respond to oncolytic viruses will be required to understand exposure and dose-response. [5]

Lastly, working with immunocompromised populations requires designing effective clinical trials and determining appropriate dosing regimens.

The market for oncolytic viruses currently has few approved therapies. However, the market is expected to grow rapidly over the next decade, with a projected CAGR of 27% from 2023 to 2033 [6].