Professor Chen Yu: Attacking poison with poison, oncolytic virus combination therapy is expected to revolutionize the treatment pattern of melanoma

Melanoma is a highly aggressive malignant tumor, the incidence of which is increasing year by year, and the degree of malignancy is high, which is prone to metastasis
.
Prior to the advent of targeted therapy and immunotherapy, patients with advanced melanoma had a very poor prognosis, with a 5-year survival rate of less than 10%^1,2
.
Coinciding with the perfect conclusion of the European Society of Oncology (ESMO) Annual Conference, the "research on oncolytic virus (recombinant human adenovirus type 5) combined with programmed cell death protein-1 (PD-1) monoclonal antibody in the treatment of advanced melanoma patients who have failed previous immunotherapy" was unveiled on the international stage
in the form of e-Poster.
In this regard, Professor Chen Yu of Fujian Cancer Hospital was invited by Yimaitong to take stock of the diagnosis and treatment status of melanoma and interpret the application prospect
of oncolytic virus in melanoma.

Expert profiles

Professor Chen Yu

• Doctor/Postdoctoral Fellow in Oncology, Fujian Cancer Hospital, Deputy Director of Internal Medicine, Associate Chief Physician/Associate Professor, Master Supervisor

• Deputy Director of Drug Clinical Trial Institution and Head of Phase I Ward of Fujian Cancer Hospital

• Director of the subspecialty of melanoma, urological soft tissue oncology

• Deputy Director of the Hepatobiliary and Pancreatic Oncology Subspecialty

• Winner of the May Fourth Youth Medal of Fujian Province

• Category C of high-level talents in Fujian Province

• Standing Committee Member of Melanoma Expert Committee of Chinese Society of Clinical Oncology (CSCO).
  

• Member of the Expert Committee of Urothelial Carcinoma of the Chinese Society of Clinical Oncology (CSCO).
  

• Member of the Liver Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
  

• Member of the Immunotherapy Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
  

• Member of the Medical Oncology Expert Committee of the Oncology Branch of the Chinese Medical Association

• Standing director of the first youth council of the Chinese Anti-Cancer Association

• Executive Vice President of the First Youth Council of Fujian Anti-Cancer Association

• Chairman of the first melanoma professional committee of Fujian Anti-Cancer Association

• Vice Chairman of the Second Medical Oncology Professional Committee of Fujian Anti-Cancer Association

• He is the author of "CSCO Melanoma Diagnosis and Treatment Guidelines", "CSCO Urothelial Cancer Diagnosis and Treatment Guidelines", and "CSCO Primary Liver Cancer Diagnosis and Treatment Guidelines", and an expert in the quality control of melanoma single disease of the National Health Commission

The long road is long, and melanoma in China is unique

Further exploration of new therapies is still needed

Professor Chen Yu

Fujian Cancer Hospital

Professor Chen Yu pointed out that according to the global circulation data in 2020, the incidence of melanoma in China ranks 11th in the world, while the mortality rate ranks second, due to the huge base of Chinese, the number of new patients is as high as tens of thousands every year
.
The high mortality rate of melanoma in China is closely related
to the characteristics of the disease and the popularity of standardized diagnosis and treatment.
Different from European and American countries with cutaneous melanoma as the main subtype, more than half of melanoma patients in China belong to the acral subtype and mucosal subtype, and the genomics, pathological subtype and epidemiology of this subtype are significantly different from cutaneous melanoma, such as low TMB (tumor mutation burden), high aggressiveness, and higher
risk of distant metastasis.

In the previous era of melanoma chemotherapy, the 5-year survival rate was less than 10%.

With the rise of the concept of precision medicine, new therapeutic methods such as targeting and immunity developed on the basis of genes, signaling pathways, molecular typing, etc.
have successively made major breakthroughs in the field of solid tumors, especially melanoma, breaking the survival dilemma of ^treatment3
.
Professor Chen Yu introduced that targeted no-therapy has significantly improved the 5-year survival rate of cutaneous melanoma, especially the 5-year survival rate of BRAF-mutated melanoma patients is as high as more than
40%.
Due to the iterative update of immunotherapy strategies and concepts, the 5-year survival rate of double free treatment of cutaneous melanoma has exceeded 50%, and even reached 60%.

However, based on the disease characteristics of acral and mucosal melanoma in China, the incidence of BRAF mutations of the two subtypes of melanoma is much lower than that of cutaneous melanoma, and the effective rate of PD-1 treatment often does not exceed 20%.

Therefore, the diagnosis and treatment of melanoma still has a long way to go, and it is urgent to explore treatment options
that meet the characteristics of melanoma disease in China.

Oncolytic viruses are beginning to see

Or into melanoma to break the key to the game

Professor Chen Yu

Fujian Cancer Hospital

Immunotherapy not only has immune checkpoint inhibitors, but also new immunotherapies such as oncolytic viruses have gradually "killed" melanoma
.
Oncolytic viruses are a class of natural or recombinant viruses that selectively infect and kill tumor cells without damaging normal cells, directly infecting and lysing tumor cells while releasing more antigens to activate the local immune microenvironment
.
Professor Chen pointed out that based on this characteristic, oncolytic viruses have synergistic effects
when combined with chemotherapy, radiotherapy, immune checkpoint inhibitors, cytokines, etc.
Oncolytic virus is a promising anti-tumor treatment, which will be fully explored
in various solid tumor fields.

Up to now, there are four oncolytic virus drugs on the market, and their mainstream products include: H101 (recombinant human adenovirus type 5, approved indication is nasopharyngeal carcinoma), T-VEC (I HERPES SIMPLEX VIRUS, APPROVED INDICATION: MELANOMA) and G47Δ (I herpes simplex virus, approved indication: glioma).

。 Professor Chen introduced that H101 is an oncolytic virus constructed with human adenovirus type 5 as the vector, which has the ability to accurately target and infect tumor cells by deleting some gene fragments in the E1B-55 kD and E3 regions, which has little impact on normal cells, and enhances its local immune induction ability, enhances its peripheral blood clearance, and improves safety
.

Precision medicine drives the field

It is imperative to standardize the diagnosis and treatment of melanoma

Professor Chen Yu

Fujian Cancer Hospital

Professor Chen emphasized that Chinese melanoma patients are mainly acral and mucosal subtypes, and there are a large number of primary and acquired drug
resistance in clinical immunotherapy.
The initial response rate of accomal melanoma is only about 10%-15%, while the initial response rate of mucosal melanoma alone is less than 5%, that is, more than 80% of patients have primary drug resistance, and even patients who respond have acquired resistance
in subsequent treatment.
Due to the accessibility of drugs, the rescue treatment methods after immunoresistance in melanoma patients are very limited, especially in patients with acral melanoma, who are prone to subcutaneous metastases that are difficult to resect by surgery and lesions with regional lymph node recurrence, which can be used as an exploration model
for oncolytic virus treatment of malignant tumors.

Based on this background, Professor Chen shared a "single-center, single-arm, prospective study of oncolytic virus (recombinant human adenovirus type 5) combined with PD-1 monoclonal antibody in patients with advanced melanoma who have failed previous immunotherapy", which estimates to recruit 10 patients with advanced melanoma who have failed previous immunotherapy to receive H101 combined with PD-1 monoclonal antibody
.
According to the individual patient's situation, intratumorous injection of H101 on the first day of each cycle, a two-week cycle, a total of 4 cycles
.
In addition, PD-1 monoclonal antibody is administered intravenously at a dose of 3 mg/kg
within 48 hours of H101 injection.
The primary endpoint of the study was objective response rate (ORR), with secondary endpoints including duration of response (DOR), disease control rate (DCR), overall survival (OS), quality of life (QOL), and adverse events (AEs)⁴
.

Fig.
1 H101 study design

Professor Chen expressed the hope that this research can lay a foundation for the future combination therapy of oncolytic viruses, and at the same time, its center has made great progress with the support, help and promotion of many sister hospitals in China, and hopes that in the future, through the improvement and strengthening of the discipline system, the standardized diagnosis and treatment of melanoma will be further promoted to benefit more patients
.

References:

LI Wei, HU Jiali, WANG Kai, et al.
Research status and prospect of immunotherapy for melanoma[J].
Chinese Journal of Clinical Pharmacology and Therapeutics, 2021.

WANG Yiqian, ZHOU Jialei, BAI Kaiwen, et al.
Research progress on pathogenesis and treatment of melanoma[J].
Pharmaceutical Biotechnology, 2019(4):5.

[3] ZHANG Jiaran, QI Zhonghui, SI Lu.
Current status and progress of treatment of advanced malignant melanoma under the background of precision medicine[J].
Chinese Journal of Cancer Biotherapy, 2021, 28(4):8.

[4]  Jing Lin, Bin Lan, Ling Chen,Recombinant human adenovirus type 5 combined with anti‐PD‐1 monoclonal antibody in the treatment of patients with advanced melanoma with previous immunotherapy failure: a single-site, single-arm, prospective study.
2022ESMO.