Are We Nearly There Yet?

When people talk about cancer immunotherapy, they are usually referring to immune checkpoint inhibitors, a class of drugs that is now widely used in the treatment of solid tumors. Oncolytic viruses, while under the immunotherapy umbrella, are far less well-known, even though the concept of using a virus to destroy a tumor is not a particularly new one. Scientists have understood for decades that these microorganisms can cause tumor cell death, but their translation to the clinic has been slow.

Oncolytic viruses mediate antitumor activity through a dual mechanism of action. First, they selectively replicate within the tumor cells, causing lysis and immunogenic cell death. Then, the rupture of the cancer cells releases tumor-derived antigens that stimulate a systemic antitumor immune response. To boost natural antitumor activity, scientists have engineered oncolytic viruses to express pro-inflammatory cytokines that promote immune cell accumulation, or suicide genes that can make the cells more sensitive to lysis or to other cancer drugs.

However, to date only four such viruses have garnered regulatory approval worldwide. The first to be commercialized was H101, under the brand name Oncorine, developed by Shanghai Sunway Biotech. It is a recombinant human adenovirus type 5 that has had two gene fragments removed. Deletion of these fragments restricts virus replication to tumor cells, ensuring selective cytotoxicity. H101 was approved by the Chinese State Food and Drug Administration in 2005 for intratumoral use in patients with nasopharyngeal carcinoma in combination with chemotherapy, after a Phase III clinical trial showed that the response to chemotherapy almost doubled with the addition of H101.¹ More recent publications show that the treatment is now being tested against cervical and colorectal cancers.

In 2004, an echovirus-based treatment for stage I–II melanoma, ECHO-7, was registered with the Latvian State Agency for Medicinal Products. It was also approved for use in Georgia in 2015 and Armenia in 2016.² The treatment was reported to decrease the risk for disease progression relative to other experimental immunotherapies but had its registration in Latvia suspended in 2019 when “quality defects” were detected during routine quality control testing.^{3, 4}

The third oncolytic virus to gain regulatory approval, Amgen’s talimogene laherparepvec (T-VEC; brand name Imlygic), has arguably become the most well-known and widely used. T-VEC is an attenuated oncolytic herpes simplex virus type 1 (HSV1) that encodes granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that stimulates an antitumor immune response. It was approved by the U.S. Food and Drug Administration (FDA) in 2015 for intratumoral treatment of unresectable stage IIIB–IV melanoma based on Phase III study data that showed a durable response in 16.3% of patients, compared with 2.1% in a group treated with GM-CSF. Approvals in Europe (2015), Australia (2016), and Israel (2017) followed shortly thereafter,² and trials are now under way for other indications, including breast cancer.

It was another four years before teserpaturev (Delytact) was approved by Japanese authorities in 2021. The triple-mutated oncolytic HSV1 was developed by Daiichi Sankyo and received conditional approval for the intratumoral treatment of recurrent glioblastoma based on the results of a single-arm Phase II clinical trial. Daiichi Sankyo now needs to conduct a post-marketing approval condition assessment to evaluate the predicted efficacy, including survival benefits and safety, and resubmit the marketing authorization application within seven years.

Slow progress

Although these four treatments have reached the clinic, “oncolytic virus therapy has not yet delivered on its promise,” says Stephen Russell, CEO of Vyriad, a clinical-stage company developing proprietary oncolytic virus therapies in Rochester, Minnesota. Russell’s lifelong goal has been to develop viruses and use them to treat cancer. He says that there was a lot of excitement around oncolytic immunotherapy when T-VEC was approved, but this has since dwindled because, despite much research, “people haven’t really found what they’ve been looking for.”

Russell and other experts who have been working with oncolytic viruses for decades cite reasons for the slow progress that are complex and multifactorial.

“I think there was a lack of education around oncolytic viruses when T-VEC was approved, what they do and how to work with them. In addition, I think there is a perception that T-VEC was not a commercial success, although I am not sure that’s exactly true,” says Howard Kaufman, a physician–researcher at the Center for Melanoma at Massachusetts General Hospital in Boston and surgical lecturer at Harvard Medical School who has played a key role in the T-VEC clinical trials. “I think the physicians that pick it up and use it actually really like it, but it took a little while to define the right population for treatment,” he adds.

Other factors that have played a part include the need to determine the best study designs and endpoints, to pick the most suitable oncolytic virus for the tumor being targeted, and in the early days, biosafety concerns. In their unmodified forms, many of the oncolytic viruses cause diseases in humans that could be particularly dangerous for an already immunocompromised patient with cancer. Thankfully, “the field in general has had a very good safety record,” notes Kaufman. The viruses have been developed to be very specific to tumor cells and not to cause systemic infection.

It is unclear when the next approval will come, but one of the frontrunners in the race is CG Oncology, a company whose research team, according to Chief Medical Officer James Burke, has “probably conducted more clinical studies and treated more patients with oncolytic viruses worldwide than any other group in the space.”

CG Oncology’s lead candidate is cretostimogene grenadenorep­vec (CG0070), a serotype 5 adenovirus engineered to replicate and express GM-CSF selectively in tumors. It is currently in a Phase III trial (BOND-003) utilizing intravesical delivery to treat BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Earlier Phase I and II studies showed complete response rates of between 45% and 65%, which “really set the stage for the Phase III study,” says Burke. He adds that enrollment of that trial is almost complete, with initial data expected in about a year and an FDA Biologics License Application to follow thereafter.

CG0070 is also being studied in combination with pembrolizumab in the Phase II CORE-001 among people with NMIBC, while the CORE-002 Phase II trial is evaluating the treatment in combination with nivolumab for patients with muscle invasive bladder cancer.

Results from CORE-001, presented at the 2023 annual meeting of the American Urological Association, showed a complete response rate of 85% at 3 months and 68% at 12 months.⁷

Roger Li, lead study investigator and urologic oncologist at the Moffitt Cancer Center in Tampa, Florida, says that these results “are far better than any of the other trials that we’ve seen in terms of long-term durable response, and I truly think that’s what patients want. They’re not necessarily looking to have a response to the treatment within three months, they’re more interested in having a durable response so that they can keep their bladders and not risk any cancer progression.”

If approved, Burke thinks that urologists will “initiate therapy with intravesical monotherapy and then at failure add pembrolizumab.” For patients with more advanced or high-risk disease, “urologists may start with the combination,” he suggests.

Unanswered questions

While work continues to find the next oncolytic virus therapy to make a clinical impact, several unanswered questions remain, including when the treatment should be deployed. Clinical trials of novel therapeutics typically focus on patients with advanced cancers for whom all other treatment avenues have been explored, and this has also been the case for oncolytic viruses. Kaufman, however, believes that their place may be earlier in the treatment journey, as a neoadjuvant therapy. He predicts that “getting to earlier stage cancers and neoadjuvant therapy for the more advanced disease is going to be the sweet spot for these agents because they get you that personalized immune response you need.”

CORE-002 is one example of a neoadjuvant trial currently underway, while a recent review highlights several more groups using oncolytic virotherapy in the neoadjuvant setting. Many of these involve T-VEC and have shown this approach can improve therapeutic outcomes and should continue to be explored.⁸

Another unanswered question is how scientists and companies should go about choosing the optimal virus for their target cancer and patient. Biomarkers are commonplace in other areas of cancer therapy, but not so for oncolytic therapies. Nonetheless, work is ongoing, and it is something that groups developing the viruses are keen to pursue. Indeed, a recent study in people with melanoma found tumor cells that had lost the ability to express the proteins JAK1 and JAK2 were resistant to traditional anti-PD-1 immunotherapy but were much more sensitive to oncolytic virus infection, suggesting that JAK1 and JAK2 expression may be an important biomarker of oncolytic virus activity. STING, a protein that detects the presence of DNA viruses in cells, has also been suggested as a potential biomarker after a study carried out in Kaufman’s laboratory showed that loss of STING expression was associated with improved oncolytic activity of T-VEC in vitro.¹⁰

Future directions

To date, all oncolytic viruses given regulatory approval and the majority in development are administered intratumorally. This has the advantage of delivering the treatment to exactly where it needs to be and avoiding the systemic immune response, but is not without its technical difficulties for the clinician administering the medication.

Systemic delivery, on the other hand, would be far more convenient, but the virus needs to avoid being cleared by the immune system before it reaches the tumor. One way to approach this is to use a virus like VSV, which typically infects cattle and other hoofed animals, meaning that humans are unlikely to have latent immunity.

Vyriad’s lead candidate, Voyager-V1, is an oncolytic VSV that has been tested in almost 200 patients in various exploratory settings and has shown a strong signal in cases with peripheral T cell lymphoma. The virus, which is being trialed in partnership with Regeneron, has been modified to encode interferon beta, which drives a local inflammatory response to the tumor. It is given as a one-time 30-minute infusion in hospital, and in a Phase I study, three of nine patients had a complete response, with a further two experiencing a partial response, for an overall response rate of 55%.¹¹

“On the basis of that, we’re now proceeding with a 20-patient expansion cohort,” says Russell. “And if the signal holds, then I think we’re in position to go for registration trial.”

Vyriad is not currently modifying VSV to help it evade the immune system, but the company isn’t ruling this out in the future. Other groups looking into systemic administration have tried putting the virus inside a nanoparticle so that it can avoid attack until it reaches the tumor, or inside mesenchymal stem cells where the virus is hidden from the immune system and trafficked to the tumor site. There are also teams looking at magnetic targeting or ultrasound-mediated delivery, but all of these approaches are still in early stages of development.

Regardless of how they are delivered, Russell believes that oncolytic viruses will become increasingly important as a frontline cancer therapy in the next decade. “Everything I see preclinically tells me that a single dose of an oncolytic virus changes the game when you then give immunotherapy,” he remarks.

There is also huge promise for precision medicine in the possibility of arming viruses with tumor-specific therapies that can be precisely delivered into a tumor microenvironment while leaving healthy tissue unscathed.

References:

1. Xia, Z-J, Chang J-H, Zhang L, et al. Ai Zheng 2004; 23: 1666–1670.
2. Shalout SZ, Miller DM, Emerick KS, et al. Nat Rev Clin Oncol 2023; 20:160–177.
3. www.zva.gov.lv/lv/jaunumi-un-publikacijas/jaunumi/aptureta-rigvir-registracija-informacija-esosajiem-pacientiem
4. www.zva.gov.lv/lv/jaunumi-un-publikacijas/jaunumi/par-zalu-rigvir-skidums-injekcijam-kvalitates-parbaudes-rezultatiem
5. Andtbacka, RHI, Kaufman HL, Collichio F, et al. J Clin Oncol 2015; 33: 2780–2788.
6. www.biopharmguy.com/links/company-by-location-viral-technology.php
7. Li R, Steinberg G, Uchio E, et al. J Urol 2023; 209: e408
8. Thomas RJ, Bartee E. J Immunother Cancer 2022; 10: e004462.
9. Nguyen TT, Ramsay L, Ahanfeshar-Adams M, et al. Clin Cancer Res 2021; 27: 3432–3442.
10. Bommareddy PK, Zloza A, Rabkin SD, Kaufman, HL. OncoImmunology 2019; 8: e1591875.
11. Cook J, Peng KW, Witzig TE, et al. Blood Advances 2022; 6: 3268–3279.

Laura Cowen is a freelance medical journalist who has been covering healthcare news for over 10 years. Her main specialties are oncology and diabetes, but she has written about subjects ranging from cardiology to ophthalmology and is particularly interested in infectious diseases and public health.