Shanghai Expert Consensus on the Clinical Application of Oncolytic Viruses in the Treatment of Malignant Tumors (Version 2021)-Summary

In clinical work, most physicians lack sufficient understanding of the mechanism of action of oncolytic virus drugs and evidence-based medicine, and the clinical application lacks a unified standard.
At present, there is no expert consensus on oncolytic virus in anti-tumor treatment at home and abroad.

In view of this, led by Professor Xu Qing, Professor Lu Shun and Professor Chen Jianhua of the Shanghai Anti-Cancer Association's Tumor Immunotherapy Professional Committee and China Medical Biotechnology Association, it organized dozens of experts in the field of basic and clinical research on tumor bioimmunotherapy in Shanghai.
In recent years, the basic and clinical research results of oncolytic viruses in the field of anti-tumor therapy, combined with the actual clinical work experience of experts, from the classification of oncolytic viruses, anti-tumor mechanisms, evidence-based medical evidence for clinical applications, methods of use, and adverse reactions In terms of management and efficacy evaluation, the "Shanghai Expert Consensus on the Clinical Application of Oncolytic Viruses in the Treatment of Malignant Tumors (2021 Edition)" was compiled, which was recently published in the "Chinese Journal of Cancer", in order to provide references for clinicians to use oncolytic virus drugs.

 Oncolytic viruses are a class of natural or recombinant viruses that can selectively infect and kill tumor cells without damaging normal cells.

Compared with traditional immunotherapy, oncolytic virus therapy has the advantages of good targeting, small side effects, many ways to kill tumors, and resistance to drug resistance.

A number of clinical studies have shown that oncolytic viruses can bring clinical benefits to patients with different types, different stages of progression, and even metastatic and incurable tumors.

More importantly, when used in combination with chemotherapy, radiotherapy, immunotherapy, etc.
, it has a synergistic effect, which can make the tumor species that have poor response to immune checkpoint inhibitors and other immunotherapeutic drugs become sensitive.

 At present, dozens of oncolytic virus drugs have been developed for tumor treatment, including adenovirus, HSV-1, vaccinia virus, reovirus, and newcastle disease virus.
virus) and so on.

In clinical trials published from 2000 to 2020, the five most commonly used oncolytic viruses are adenovirus, HSV-1, reovirus, vaccinia virus and Newcastle disease virus.

This consensus mainly introduces two oncolytic virus drugs that have completed phase III clinical studies and have been approved for marketing: H101 (recombinant human adenovirus type 5) and T-VEC (HSV-1) (Table 1).

 1.
Evidence-based medicine evidence 01 Approved indication ➤H101: A multi-center phase III clinical study of nasopharyngeal carcinoma in China compared the therapeutic effects and adverse reactions of intratumoral injection of H101 combined with chemotherapy and chemotherapy alone.
The study included 160 Among the patients with head, neck, and esophageal squamous cell carcinoma, 91 of them were nasopharyngeal carcinoma.
All the selected patients received chemotherapy.

The results showed that in terms of target lesions, among the 123 patients who met the trial protocol and completed the trial, the complete response (CR) rate and partial response (PR) rate (CR+PR) of H101 combined with chemotherapy were effective ) Was significantly higher than that of the chemotherapy alone group (72.
7% vs 40.
4%).
From the overall efficacy of the subjects, the effective rate of the combined group was also significantly higher than that of the chemotherapy alone group (71.
2% vs 35.
1%).

The adverse reactions that occurred during the test mainly included fever, local reactions at the injection site, flu-like symptoms, decreased white blood cells, decreased platelets, abnormal liver and kidney function, hair loss, nausea and vomiting, etc.

 In 2005, the National Medical Products Administration approved the oncolytic adenovirus drug H101 combined with chemotherapeutic drugs for the treatment of advanced nasopharyngeal carcinoma.
This is also the world's first oncolytic virus treatment with clinical indications approved.

 ➤T-VEC: A phase III clinical trial of melanoma randomly assigned 436 patients with stage IIIB to IV melanoma that cannot be surgically removed to the intratumor injection T-VEC group at a ratio of 2:1 (n=295) And subcutaneous injection of GM-CSF group (n=141).

The results showed that the durable response rate (DRR) (16.
3% vs 2.
1%, P<0.
001) and the objective response rate (ORR) (26.
4% vs 5.
7%) of the patients in the T-VEC group were ) And median overall survival (OS) (23.
3 months vs 18.
9 months, P=0.
051) were higher than those of the GM-CSF subcutaneous injection control group; and the efficacy of T-VEC was in ⅢB, ⅢC or Stage IV (M1a stage) is most pronounced in patients and patients who have not received previous treatment; the common adverse reactions associated with T-VEC use are fatigue, chills and fever, and the grade 3 or 4 adverse reactions with an incidence of ≥ 2% are honeycomb Weaving inflammation (2.
1%), no treatment-related fatal adverse reactions occurred.

 A phase I clinical trial published in Cell magazine in 2017 proposed a new combination drug regimen, namely oncolytic virus combined with programmed death [protein]-1 (programmed death-1, PD-1) antibody Paboli Pembrolizumab (pembrolizumab) in the treatment of patients with advanced melanoma.

The results showed that T-VEC combined with pembrolizumab was well tolerated.
Common adverse reactions were fatigue, fever and chills, and no dose-limiting toxicity occurred.

ORR was 62%, CR rate was 33%; CD8+ T cells increased and the expression of PD-L1 protein and IFN-γ increased after combined treatment, suggesting that oncolytic virus therapy can improve PD-1 by changing the tumor microenvironment The efficacy of antibodies.

 A phase II clinical trial evaluated the safety and effectiveness of T-VEC combined with CTLA-4 inhibitors in the treatment of advanced melanoma.

The results showed that the ORR of the T-VEC and ipilimumab combination therapy group was higher than that of the ipilimumab monotherapy group (39% vs 18%, P=0.
002); the response of the combination group was not limited to the injection lesion ; The combined group reduced the organ pathology by 52%, and the single-agent group reduced by 23%; common adverse reactions included fatigue (59% in the combined group, 42% in the single-agent group), chills (53% in the combined group, and single-agent group 3%) and diarrhea (42% in the combination group and 35% in the single-drug group); the incidence of ≥3 grade adverse reactions was 45% and 35%, respectively, and no treatment-related fatal adverse reactions occurred.

 Therefore, for patients with unresectable advanced melanoma, T-VEC can be considered for local treatment.

In addition, the application of T-VEC can increase the anti-tumor activity of immune checkpoint inhibitors.
In addition to local treatment, oncolytic virus combined with immune checkpoint inhibitor therapy is recommended for advanced malignant melanoma.

In 2015, the U.
S.
FDA approved T-VEC for the local treatment of melanoma patients who recurred after surgical resection.
This is also the first oncolytic virus treatment program approved in the United States.

02Explore indications ➤H101: Transarterial chemoembolization (TACE) for hepatocellular carcinoma is the most commonly used treatment for patients with advanced hepatocellular carcinoma.

Studies have reviewed and analyzed the efficacy of TACE alone or in combination with adenovirus H101 in the treatment of hepatocellular carcinoma.
A total of 175 patients with hepatocellular carcinoma that cannot be surgically removed were included.

The results showed that compared with TACE alone (n=88), TACE combined with H101 treatment (n=87) can significantly prolong the patient's OS (12.
8 months vs 11.
6 months, P=0.
046) and PFS (10.
49 months) vs 9.
72 months, P=0.
044), improved CR rate (14.
8% vs 28.
7%, P=0.
017) and reduced disease progression (PD) rate (25.
0% vs 12.
6%, P=0.
011).

Neither group had Grade 4 clinical toxicity or surgery-related death (30 days) due to liver failure, and no serious complications or Grade 3 to 4 liver toxicity occurred within 1 month after treatment.

There was no significant difference in the incidence of treatment-related adverse reactions between the two groups (P>0.
05).

 2.
Method of use 3.
Efficacy evaluation The currently commonly used clinical efficacy evaluation criteria of anti-tumor drugs include traditional WHO standards, response evaluation criteria in solid tumors (Response Evaluation Criteria in Solid Tumors, RECIST) and improved RECIST developed on this basis (Modified RECIST, mRECIST) (Table 3).

 4.
Summary As an emerging tumor biological immunotherapy method, oncolytic viruses have been approved for use by regulatory agencies in China and many European and American countries.

Oncolytic viruses kill cancer cells through a variety of mechanisms.

A large number of clinical studies have confirmed that it has a good record of clinical safety medication.
Its infection of tumor cells enhances the body's anti-tumor immune response and can produce a relatively long-lasting response.
Oncolytic viruses are particularly relevant to chemotherapy, radiotherapy, and targeted therapy.
It is a combination of immunotherapy, which can improve the efficacy of original drugs.

However, the system and physical barriers in the tumor microenvironment are still the main obstacles affecting the clinical efficacy of oncolytic viruses, and this is also the focus of its future basic and clinical research.

It is believed that with the progress of future research, more cancer patients will benefit from oncolytic virus treatment.

 References: Xu Qing, Lu Shun, Zhu Huiyan, Zheng Leizhen, Jiang Bin, Liang Xiaohua, Zhao Ren, Zhou Zhen, Wang Mei, Chen Jianhua, Xu Yu, Qin Huanlong, Wei Yuquan.
Shanghai expert consensus on the clinical application of oncolytic viruses in the treatment of malignant tumors ( 2021 edition) [J].
Chinese Journal of Cancer, 2021, 31(3): 231-240.
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