Mechanism · Oncolytic virotherapy
How a virus kills cancer,
and wakes up the immune system.
Oncolytic viruses work on two levels. They replicate inside cancer cells until the cells burst, and the dying tumour can draw immune cells in. Here is how H101 is engineered, and what was actually measured in patients.
Quick answer
How do oncolytic viruses work?
An oncolytic virus is engineered to complete its replication cycle mainly in cancer cells. Inside a tumour cell it multiplies until the cell bursts (oncolysis), releasing new virus that can infect neighbouring tumour cells. Tumour lysis can also stimulate immunity. In patients given H101 for malignant ascites, researchers measured falling tumour-cell density alongside rising dendritic-cell and CD8+ T-cell levels. They also detected tumour-specific T-cell responses, which is the basis for combining oncolytic viruses with PD-1 inhibitors.
E1B-55kD
Deleted gene
Basis of tumour-selective replication
Drug label; Xia 2004
E3
Deleted fragments
78.3–85.8 map units
Drug label
↓ Tumour cells
Days 7 & 14
Significant fall in tumour-cell density in ascites
Zhang et al., Mol Ther Oncolytics 2022
↑ CD8+ T
Days 7 & 14
Significant rise in CD8+ T-cell density
Zhang et al., Mol Ther Oncolytics 2022
↑ DC
Dendritic cells
Increased after intraperitoneal H101
Zhang et al., Mol Ther Oncolytics 2022
↑ PD-1
Day 7
On Treg and exhausted CD4+ T cells
Zhang et al., Mol Ther Oncolytics 2022
Mechanisms
Two ways oncolytic viruses fight tumours.
1 · Selective oncolysis
The virus replicates in tumour cells and bursts them, and the new virus particles can spread to nearby cancer cells.
Local tumour destruction
2 · Immune activation
Tumour lysis can recruit dendritic cells and CD8+ T cells and prime tumour-specific T-cell responses. This is the rationale for combining with checkpoint inhibitors.
'Cold' → 'hot'
Selectivity
Why an E1B-55kD-deleted adenovirus favours tumour cells
A normal adenovirus uses its E1B-55kD protein to take over the host cell. H101 has this gene deleted. When H101 was developed, the rationale was that the virus would replicate in p53-mutated tumour cells and spare normal tissue.
Later work on ONYX-015, a closely related E1B-55kD-deleted adenovirus, refined this picture. O'Shea and colleagues (Cancer Cell, 2004) showed that tumour selectivity depends mainly on the export of late viral RNA out of the nucleus, not on p53 status. Normal cells need E1B-55kD for that export step, while many tumour cells can complete it without the viral protein.
| Step | Normal cell | Tumour cell |
|---|---|---|
| Virus entry and early gene expression | Yes | Yes |
| Late viral mRNA exported to cytoplasm | Impaired without E1B-55kD | Supported by the tumour cell |
| Assembly of new virus | Limited | Efficient |
| Outcome | Replication restricted | Cell lysis; virus spreads to neighbouring tumour cells |
This model was established for ONYX-015, which shares H101's E1B-55kD deletion. Selectivity is strong but not absolute.
Immunology
Turning 'cold' tumours into 'hot' tumours
Many solid tumours are immunologically 'cold': few effector T cells reach them, and checkpoint inhibitors such as PD-1 drugs work poorly. Oncolytic viruses are studied as a way to inflame these tumours (reviewed by Muscolini et al., 2020).
The most detailed H101 data come from Fudan University Shanghai Cancer Center. It was a retrospective study of 40 patients with malignant ascites treated with intraperitoneal H101, with immune profiling in 6 patients. The changes the researchers reported are below.
| Finding | Detail |
|---|---|
| Tumour-cell depletion | Tumour-cell density fell significantly at days 7 and 14 (immunocytochemistry, n=6) |
| CD8+ T cells | CD8+ T-cell density rose significantly; the CD8+ effector-memory fraction increased by day 14 |
| Dendritic cells | DC fractions increased; two responders showed DC increases at day 7 |
| Tumour-specific response | IFN-γ ELISpot showed tumour-specific CD8+ T-cell activation at day 14 (1 patient) |
| PD-1 | Increased at day 7, notably on Treg and exhausted CD4+ T cells |
| PD-L1 | PD-L1+ myeloid cells increased in 3 of 4 responders |
| Anti-adenovirus antibodies | All 6 profiled patients had pre-existing anti-adenovirus IgG |
The authors interpreted the PD-1/PD-L1 rise as acquired immune resistance, which supports trials combining H101 with checkpoint inhibitors. Small sample; individual responses varied.
FAQ
Oncolytic virus mechanism — answered.
- How does a virus kill cancer cells without harming normal cells?
- Oncolytic viruses are engineered to depend on features that tumour cells have and healthy cells lack. H101 lacks the E1B-55kD gene. Research on the closely related ONYX-015 showed that normal cells need this viral protein to export late viral RNA and build new virus, while many tumour cells don't. The virus therefore replicates mainly in tumour cells. Selectivity is strong but not absolute.
- What is a 'cold' vs 'hot' tumour?
- A 'hot' tumour is infiltrated by immune cells, especially cytotoxic T cells, and tends to respond better to checkpoint inhibitors. A 'cold' tumour has few T cells, so immunotherapy often fails. Oncolytic viruses are studied as a way to inflame cold tumours. In the H101 malignant-ascites study, CD8+ T cells and dendritic cells increased after treatment.
- Why combine oncolytic viruses with PD-1 inhibitors?
- In the Fudan study, PD-1 and PD-L1 expression rose after H101. That is a brake the immune system applies in response to inflammation, and it is exactly what PD-1/PD-L1 drugs block. This finding underpins trials such as H101 + nivolumab in refractory liver cancer.
- Will my immune system just destroy the virus?
- Pre-existing immunity is common. All six patients profiled in the Fudan study already had anti-adenovirus antibodies. Viral infection was detected in 3 of 6 patients at day 7 and rarely at day 14. In the published studies, H101 is delivered locally — into the tumour, the hepatic artery or the peritoneal cavity.
Related guides
Oncolytic Virus Therapy (hub)
Overview: what it is, who it may suit, how it's used in China.
Read the guideOncorine (H101) drug profile
Approval, genetic construct, approved indication and milestones.
Read the guideH101 + TACE for liver cancer
Evidence, guideline status and treatment protocol for HCC.
Read the guideH101 + PD-1 immunotherapy
Combination data, malignant ascites and immune-microenvironment changes.
Read the guideSafety & side effects
Adverse-event rates from the Phase III trial and combination studies.
Read the guideClinical evidence & guidelines
Key studies, ASCO 2024 abstracts and three Chinese consensus documents.
Read the guideOncology second opinion
Senior Chinese oncologist reviews your imaging and pathology remotely.
Read the guideSources
References
- Oncorine (重组人5型腺病毒注射液) prescribing information, 国药准字 S20060027 — indication: advanced nasopharyngeal carcinoma unresponsive to radiotherapy or chemoradiotherapy, in combination with 5-FU/cisplatin palliative chemotherapy; construct: E1B-55kD and E3 (78.3–85.8 mu) gene fragments deleted.
- Xia ZJ, Chang JH, et al. Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus. Ai Zheng. 2004;23(12):1666–1670.
- Lin XJ, Li QJ, Lao XM, Yang H, Li SP. Transarterial injection of recombinant human type-5 adenovirus H101 in combination with transarterial chemoembolization (TACE) improves overall and progressive-free survival in unresectable hepatocellular carcinoma (HCC). BMC Cancer. 2015;15:707.
- O'Shea CC, et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell. 2004;6(6):611–623.
- Muscolini M, et al. Oncolytic immunotherapy: can't start a fire without a spark. Cytokine Growth Factor Rev. 2020;56:94–101.
- Zhang Y, Qian L, Chen K, et al. Intraperitoneal oncolytic virotherapy for patients with malignant ascites: characterization of clinical efficacy and antitumor immune response. Mol Ther Oncolytics. 2022;25:31–42.
Want to know if your tumour
is a candidate?
Mechanism is only half the question. The other half is whether your tumour type, location and liver function suit the treatment. Send your records for a written review from a partner oncologist.
This page is for general education only and is not medical advice. Oncolytic virus therapy is not suitable for every patient or every cancer. In China, Oncorine (H101) is approved only for advanced nasopharyngeal carcinoma in combination with chemotherapy; other uses described here are supported by retrospective studies, small trials, conference abstracts or expert consensus rather than large randomised trials. Treatment decisions are made by the treating oncologist after reviewing your records. We are an independent patient-coordination service and are not affiliated with the manufacturer.