Despite the billions of dollars dedicated to cancer research every year, fighting the disease remains an uphill battle. Researchers are constantly seeking to add new therapeutics to the toolkit to establish more effective regimens that cause fewer side effects. That’s where a quietly progressing approach comes in: oncolytic viruses. Oncolytic viruses (OVs) are designed to selectively target and kill cancer cells while sparing normal, healthy cells. They tend to cause only mild side effects in patients. While they have been the subject of cancer therapeutic research for decades, OVs somehow remain under the radar, while cell therapies and other advanced therapeutics capture the headlines. Recent updates may change that. The steady progress of hundreds of early-stage clinical trials and ongoing post-market updates from the handful of approved OV therapies are reasons to take a closer look at this field.

Cancer vs. Virus

Oncolytic viruses are typically benign viruses such as herpes simplex or adenoviruses. Once inside the tumor, they replicate within and eventually lyse the tumor cells. The immune system recognizes and targets the cellular debris, leaving cancer cells to face an onslaught from two fronts: from the virus that is infecting them and from a full-on immune response. Put another way, oncolytic viruses promote both regional and systemic antitumor immunity. While the anti-cancer response is powerful, oncolytic viruses generally do not cause extreme side effects. Patients generally experience symptoms like that of a cold or mild flu.

There’s no denying it: it’s an elegant system. That said, there are a couple of complications that researchers have had to navigate to optimize their therapeutics, delaying the progress of clinical trials:

1. Naturally occurring oncolytic viruses can be potent but are limited in number. To widen the available pool, recombinant oncolytic viruses must be engineered to enhance the immune response and inhibit tumor neovascularization, tumor metabolism, and other aspects of the malicious tumor microenvironment.
2. Since the oncolytic activity of these viruses is so dependent on the body’s natural immune response, they may not work as well in patients who have already undergone chemotherapies that impair their immune systems. However, many patients recruited to clinical trials have already undergone these types of treatments and exhausted all other options.
3. Naked oncolytic viruses injected into the human body are targeted and destroyed by the immune system, too, and on their own, are quickly degraded as they work to infect the tumor. For this reason, the most popular mode of delivery is injection directly into the tumor, which places the virus squarely where it needs to be to do its job.

In spite of these challenges, four oncolytic virus therapies have been approved globally (although only one, T-VEC, has been approved by the U.S. Food and Drug Administration).

Pioneers in the Field

The four approved therapies — and countless other drug candidates in clinical trials — use a variety of strategies that enhance oncolytic viruses themselves and help them work better with the immune system. Below is a summary of the four approved therapies and the clinical trial results that earned them regulatory approval.

1. Rigvir, for the treatment of melanoma, was the first oncolytic virus therapy to be registered in 2004 in Latvia and subsequently gained approval in Georgia, Armenia, and Uzbekistan. However, it never gained widespread use because many key studies about it were published in Russian and Latvian at a time when those countries were behind the Iron Curtain. It uses an unmodified, naturally occurring oncolytic Enteric Cytopathogenic Human Orphan type 7 (ECHO-7) picornavirus, selected and adapted over multiple rounds of tumor exposure to combat melanoma. It is injected intramuscularly rather than into the tumor in approximately 33 doses over three years. In 50 years of preclinical and clinical studies, no one has ever stopped treatment because of side effects. Tests demonstrating efficacy leading up to its approval involved over 700 cancer patients: 540 melanoma patients, 90 patients with late-stage stomach cancer, and 60 with other cancers. The control group was treated with a relevant immunotherapy. When assessing 3- and 5-year survival of melanoma patients treated with Rigvir, the control patients’ overall survival was 54–57% and 42–56%, whereas in Rigvir patients it was 78–84% and 66–81%, respectively. Additionally, post-marketing studies demonstrate a 6-fold increase by Rigvir in progression-free survival in stage II melanoma patients. Further studies have shown increased survival in patients with stomach and rectal cancer when treated with Rigvir, too. Future studies may result in more widely accessible papers that may bring this drug back into consideration.
2. Oncorine (H101) gained approval in China in 2005 for the treatment of head and neck cancer in combination with chemotherapy. It is a recombinant version of the human adenovirus Type 5 injected directly into the tumor. It carries a deletion of the E1b-55kd, E3 gene fragment which allows it to selectively infect and multiply within tumor cells with a dysfunctional RB/P53 pathway. This results in an enhanced ability to mount an immune response, induce lymphocyte infiltration, and gain clearance from the immune system. Unlike many other oncolytic virus drugs, Oncorine’s developers claim that its antitumor activity is enhanced by chemotherapeutics. It gained regulatory approval following a multicenter, randomized phase 3 trial of 123 patients with head and neck cancer comparing Oncorine in combination with chemotherapy versus chemotherapy alone. Analysis of patient responses showed a statistically significant higher response rate in the Oncorine plus chemotherapy-treated group (78.8%) compared with the control group (39.6%). However, limited data are available regarding the long-term survival benefits of Oncorine, which would support greater adoption of the drug.
3. T-VEC is a Type 1 herpes simplex virus designed for the treatment of melanoma. It gained approval in Europe and Australia. It ultimately gained FDA approval in 2015 following a randomized open-label phase 3 study of 436 patients with unresectable stage IIIB to IV melanoma. Injected directly into the tumor, this modified oncolytic virus carries deletions of two nonessential viral genes that reduce pathogenicity and enhance tumor-specific replication, and it expresses a gene that codes for granulocyte-macrophage colony-stimulating factor – a protein that enhances the systemic antitumor immune response. In the study, T-VEC was compared with injection of granulocyte-macrophage colony-stimulating factor alone. Results showed that a significant number of patients (16.3%) had an objective response to T-VEC after the primary endpoint of 6 months, compared to 2.1% who received the control injection. T-VEC also improved overall survival, which was a median of 23.2 months in the T-VEC arm and 18.9 months in the control arm. Interestingly, T-VEC efficacy was strongest in patients with later stages of the disease and in those who had not yet been treated for cancer.
4. Delytact Is a ​​herpes simplex virus type 1 designed for the treatment of primary brain tumors. It was granted early-use approval in Japan in 2021. Intratumorally injected, Delytact carries a triple mutation in the viral genome. Specifically, the α47 gene and both copies of the γ34.5 gene have been deleted, and the infected cell protein 6 (ICP6) gene has been inactivated. This causes more vigorous and selective replication in cancer cells. These mutations also cause an enhanced antitumor immune response while retaining a good safety profile. ​​Delytact gained conditional approval following the results of an open-label, uncontrolled phase 2 clinical trial evaluating it in patients with residual or recurrent glioblastoma. The study included data on 16 patients. After 1 year, 92.3% of patients treated with Delytact had survived. That said, disease progression was observed in 14 of the 19 patients, and progression-free survival was on average 4.8 months. To retain its approval, the developers of Delytact are expected to conduct post-marketing studies and submit the results to the Japanese government.

Building a Case

The therapies above are just a few examples of how oncolytic viruses can be pitted against cancer. In fact, since 2001, 408 clinical trials of oncolytic viruses are ongoing or have been completed. However, 80% of these studies are either Phase 1 or 2. As more oncolytic virus-based therapies go through later-stage clinical trials and gain approval, they will continue to solidify regulatory expectations for those in earlier stages of development as they progress into Phase 3 and beyond. Additionally, promising post-market data are mounting regarding how patients are responding to each of the four approved therapies, validating new avenues of research in this area. As more of these drugs proceed through clinical trials and gain approval, it will be intriguing to see what strategies work best to improve results and save lives.