Oncolytic viruses in cancer treatment

Naturally occurring oncolytic viruses, which replicate in tumour cells and trigger apoptosis and immune responses while sparing healthy cells, were first discovered at the turn of the 19th century. The resulting interest in their use as cancer therapeutics is based on observations that some cancer patients with viral infections go into remission for a brief time. Research into this approach has been ongoing for over a century, with the first clinical trial of a hepatitis virus in Hodgkin’s disease in 1949, but oncolytic viruses did not reach the market until 2004 in Latvia and 2005 in China. [1-4]

The oncolytic viruses market is predicted to be worth around $399 billion by 2035, at a compound annual growth rate (CAGR) of 25.55% [5]

An introduction to oncolytic viruses

The mechanism of action of oncolytic viruses is complex and includes direct lysis of tumour cells, inducing tumour-specific T cell responses. They also have potential to bypass tumour immune evasion, which could mean lower levels of treatment resistance. Because the mechanism of action doesn’t generally overlap with that of other cancer therapies, they could be used in combination with existing and new treatments. [1-4]

Oncolytic viruses can be RNA or DNA viruses. Naturally occurring oncolytic viruses include reovirus, Newcastle disease virus, myxoma virus, picornavirus and Seneca valley virus. Genetic engineering has made it possible for researchers to boost the in vivo and antitumour immune response to the viruses, improve their replication efficiency within cancer cells, increase safety and enhance their targeting. Viruses used in a genetically engineered form include measles virus, poliovirus, vaccinia virus, adenovirus and herpes simplex virus. [2, 6]

A number of unmodified and genetically engineered oncolytic viruses have received market approval: [3, 7]

· Rigvir (ECHO-7; Picornavirus)

    o Approved in 2004 in Latvia for melanoma (unmodified virus)

· Oncorine (H101; Adenovirus serotype 5)

    o Shanghai Sunway Biotech: Approved in 2005 in China for head and neck cancer (genetically modified)

· Imlygic (T-VEC, talimogene laherparepvec; HSV-1)

    o Amgen: Approved in 2015 in the US and Europe for metastatic melanoma (genetically modified)

· DELYTACT (teserpaturev/G47Δ; HSV-1)

    o Daiichi Sankyo: Approved in 2021 in Japan for primary brain cancer (genetically modified)

The oncolytic viruses pipeline

A selection of products in development includes: [7-12]

· Adlai Nortye Biopharma

    o Pelareorep (naturally occurring dsRNA reovirus) in Phase III trials in breast cancer

· BioInvent/Transgene

    o BT-001 (oncolytic virus + anti-CTLA4 antibody) in a Phase I/IIa trial alone and in combination in solid tumours

· Candel Therapeutics

    o CAN-2409 (engineered adenovirus) in Phase III trials in prostate cancer

· CG Oncology/Kissei Pharmaceutical

    o Cretostimogene grenadenorepvec (engineered adenovirus) in Phase III trials in bladder cancer

· DNAtrix

    o DNX-2401 (engineered adenovirus) in a Phase II trial in glioblastoma multiforme

· EpicentRx [9]    

    o AdAPT-001 (engineered adenovirus) in Phase II trials alone and in combination in sarcoma

· Genelux [7]

    o Olvimulogene nanivacirepvec (engineered vaccinia virus) in Phase III trials in fallopian tube, ovarian and peritoneal cancer

· Lokon Pharma

    o LOAd 703 (engineered adenovirus) in Phase II trials in pancreatic cancer, ovarian cancer, colorectal cancer and malignant melanoma

· Oncolys Biopharma

    o Telomelysin (OBP-301; engineered adenovirus) in Phase II trials in adenocarcinoma, gastric cancer, head and neck cancer and oesophageal cancer

· Replimune

    o RP1 (vusolimogene oderparepvec; engineered HSV) in Phase II and III trials alone and in combination in melanoma, non-melanoma skin cancers and organ transplant

    o RP2 (engineered HSV) as a combination therapy in Phase II/III in uveal melanoma, and in I/II trials in solid tumours

· Surv BioPharma

    o Surv.m-CRA-1 (engineered adenovirus) in a Phase II trial in bone cancer

· Theriva Biologics

    o VCN-01 (engineered adenovirus) in Phase I and II trials alone and in combination in pancreatic and head & neck cancer and retinoblastoma

· Urogen

    o UGN-501 in preclinical development for bladder cancer

Other companies involved in oncolytic virus development include: Akamis Bio, Astellas Pharma, Binhui Biopharmaceutical, Calidi Biotherapeutics, Elicera, Hangzhou Converd, IconOVir Bio, Johnson & Johnson, KaliVir Immunotherapeutics, Kissei Pharmaceutical, Oncostar, PsiOxus Therapeutics, SillaGen, Sotio, Syneos Health, Targovax, TILT Biotherapeutics, VCN Biosciences and Virogen Biotech.

The future for oncolytic viruses

Companies developing oncolytic virus-based therapies face a number of challenges, including improving delivery to avoid the viruses being neutralised by the immune system and increasing selectivity to avoid off-target effects. The oncolytic viruses pipeline is growing globally, driven by their mechanism of action and potential as combination therapy, as well as the increasing numbers of cancer diagnoses, and research is ongoing to improve the potential first recognised many years ago.

References

1. Kelly, E. and S.J. Russell, History of oncolytic viruses: genesis to genetic engineering. Mol Ther, 2007. 15(4): p. 651-9.

2. Yuan, Z., et al., The investigation of oncolytic viruses in the field of cancer therapy. Front Oncol, 2024. 14: p. 1423143.

3. Rahman, M.M. and G. McFadden, Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy. Cancers (Basel), 2021. 13(21).

4. Yun, C.-O., J. Hong, and A.-R. Yoon, Current clinical landscape of oncolytic viruses as novel cancer immunotherapeutic and recent preclinical advancemen. Frontiers in Immunology, 2022. 13: p. 953410.

5. Oncolytic Virus Immunotherapy Market. Vantage Market Research. Last accessed: September 2023. Available from: https://www.vantagemarketresearch.com/industry-report/oncolytic-virus-immunotherapy-market-2287.

6. Oncolytic Virus Cancer Therapy: Transforming Cancer Treatment. Delveinsight. Last accessed: 5 July 2024. Available from: https://www.delveinsight.com/blog/oncolytic-virus-cancer-therapy.

7. ONCOLYTIC VIRUS THERAPY: GLOBAL CLINICAL TRIAL LANDSCAPE (2024). 2024. Available from: https://novotech-cro.com/sites/default/files/2025-01/Novotech-Oncolytic-Virus-Therapy-Whitepaper.pdf.

8. BT-001(CTLA-4,GM-CSF). BioInvent. Last accessed: 17 April 2025. Available from: https://www.bioinvent.com/en/clinical-programs/our-programs/bt-001ctla-4gm-csf.

9. 8 Late and Mid Stages Adenovirus-associated Oncolytic Virus Therapies To Watch Out. Delveinsight, 7 August 2024. Available from: https://www.delveinsight.com/blog/8-promising-adenovirus-associated-oncolytic-virus-therapies.

10. Armstrong, M. Replimune goes pivotal in uveal melanoma. ApexoOnco. Last accessed: 4 September 2024. Available from: https://www.oncologypipeline.com/apexonco/replimune-goes-pivotal-uveal-melanoma.

11. Our Pipeline. Theriva Biologics. Last accessed: 16 April 2025. Available from: https://therivabio.com/our-pipeline/.

12. Pipeline. UroGen Pharma. Last accessed: 16 April 2025. Available from: https://www.urogen.com/pipeline.