YH02 Injection for Intra-tumor Injection Therapy in Advanced Solid Tumors With Unresponsive or Failure-Treated Cases

Cancer is a disease that poses a serious threat to human health and social development. The International Agency for Research on Cancer (IARC) of the World Health Organization released the latest global cancer burden data for 2020. In 2020, there were 19.29 million new cancer cases worldwide, among which China accounted for 4.57 million cases, representing 23.7% globally. The number of cancer-related deaths worldwide reached 9.96 million in 2020, with China contributing 3 million deaths, accounting for 30% of total cancer-related fatalities. Data indicate that malignant tumor deaths account for 23.91% of all causes of death among residents, and annual medical expenditures due to malignant tumors exceed $220 billion, imposing a significant burden on patients and their families, healthcare systems, and society as a whole. Over the past decade, the cancer burden has shown a sustained upward trend, with the incidence rate of malignant tumors increasing by approximately 3.9% annually and the mortality rate rising by 2.5% annually. Furthermore, globally, due to accelerating population aging, the cancer burden is projected to increase by 50% by 2040 compared to 2020, with the number of new cancer cases reaching nearly 30 million.

In recent years, tumor immunotherapy has become a pivotal approach in cancer treatment, standing alongside chemotherapy, targeted therapy, surgery, and radiotherapy. Particularly, immune checkpoint inhibitors (ICIs) have achieved remarkable clinical success. However, overall, the response rates to these therapies remain limited and require further improvement. Tumors that respond to ICI are termed immunologically "hot tumors," whereas those that do not respond are referred to as "cold tumors." Since German scientist Jean Rommelaere first described oncolytic virus therapy as tumor immunotherapy in a 2011 publication, oncolytic viruses have gained widespread acceptance as a key branch of tumor immunotherapy. The use of oncolytic viruses to convert "cold tumors" into "hot tumors" is recognized as an effective strategy .

Oncolytic viruses possess multiple functions, including direct killing of tumor cells, induction of immune responses, and enhancement of the efficacy of other antitumor agents. Compared to conventional treatment approaches, they offer distinct advantages such as high specificity, minimal side effects, and broad efficacy against various tumor types. Oncolytic viruses are a class of naturally occurring or genetically engineered viruses capable of targeting and destroying tumor cells. The primary oncolytic viruses currently employed in cancer research include herpes simplex virus, adenovirus, and vaccinia virus. These viruses achieve specific targeting of tumor cells and self-replication by leveraging various mechanisms: abnormal expression of surface receptors, defects in surface molecules, alterations in signaling pathways within tumor cells, deletion of genes essential for viral replication in normal cells but non-essential in tumor cells, and placement of replicative genes under the control of specific promoters. This enables tumor cell lysis and death, with released viruses initiating new infection cycles. Additionally, lysed tumor cells release abundant tumor antigens, activating specific antitumor immunity to recognize and attack uninfected tumor cells. Furthermore, upon entering the body, oncolytic viruses stimulate antiviral immunity, reverse the suppressive state of immune cells in the tumor microenvironment, and redirect immune attacks toward tumor cells. Finally, oncolytic viruses can deliver therapeutic molecules or be combined with other therapies to enhance antitumor efficacy.

Human adenovirus was first isolated in 1953 from the tonsils of infants with respiratory infections. Adenoviruses can infect various mucosal tissues, including the gastrointestinal tract, respiratory system, urogenital tract, and conjunctiva [14]. Adenoviral vectors are widely used in research on prevention and treatment of genetic disorders, cancers, and infectious diseases; in addition to the commonly employed adenovirus type 5 vector, multiple other serotype adenovirus vectors have been developed. Adenovirus is an envelope-free, twenty-faced symmetrical linear double-stranded DNA virus classified by the International Commission on Viral Classification into groups A-G7 comprising 52 serotypes .Oncolytic adenoviruses, also known as conditionally replicating adenoviruses (CRADs), are genetically engineered adenoviruses capable of selectively replicating within tumor cells, ultimately causing their lysis while causing minimal damage to normal cells. The most widely used oncolytic adenoviruses belong to subtypes 2 and 5 of the Adenovirus genus within the Adenoviridae family , both classified serologically as Group C. These are enveloped double-stranded DNA viruses with a twenty-faced symmetrical structure, featuring fibrin-based cilia on their capsid surface whose size and quantity are species-specific, playing a role in receptor cell adhesion and binding. The infection process involves several key steps: first, viral particles bind to specific receptors on the host cell membrane, primarily the Coxsackievirus receptor (CAR); subsequently, they interact with integrins, enter cells via endocytosis, and shed their capsids; finally, viral DNA is released into the nucleus through nuclear pores for transcription and replication. Due to their ability to selectively replicate in tumor cells and deliver exogenous genes for expression therein, oncolytic adenoviruses have garnered significant attention in oncology therapy and represent a promising novel approach for cancer treatment. However, the use of recombinant oncolytic adenoviruses alone did not achieve the expected therapeutic efficacy; consequently, further modification of oncolytic adenoviruses has become a new research focus.

In clinical research on oncolytic adenovirus-based cancer gene therapy, the United States leads the world in this field, with several of its oncolytic adenovirus products having entered the clinical stage. Clinical studies have demonstrated that oncolytic adenovirus-based therapies will become a highly promising area of focus for future cancer gene therapy. In 2003 and 2005, China's National Medical Products Administration approved two adenovirus-based products for market release: "Jinyousheng" by Shenzhen Sainuo and "Ankerui" by Shanghai Sanwei Biotech. Clinical trials conducted with Ankerui across various solid tumors indicated favorable safety profiles and certain therapeutic efficacy when administered via intratumoral injection or pleural perfusion for treating nasopharyngeal carcinoma, hepatocellular carcinoma, pancreatic cancer, among others . Currently, most oncolytic virus drug development in China relies primarily on purchased or imported generic versions, with few companies possessing comprehensive independent design capabilities or robust R\&D capacities; overall, the design quality remains relatively low, and most products exhibit insufficient therapeutic efficacy.The preclinical pharmacological mechanism of YH02 injection is well established. By constructing a vector expressing MMP13, introducing a human S promoter, and genetically modifying the capsid protein, the virus's permeability, tumor targeting capability, and infection efficiency were significantly enhanced. Preclinical pharmacodynamic studies demonstrated that YH02 exhibits potent tumor growth inhibitory effects in various human-and murine-derived solid tumor models (including breast cancer, liver cancer, and melanoma). Given that oncolytic virus therapies already have approved products with demonstrated safety and efficacy worldwide, this study may offer potential clinical benefits for patients with advanced solid tumors who have failed standard treatments.

YH02 injection has undergone an open-label, dose-escalating, and expanded Phase I clinical study in China aimed at evaluating the safety, tolerability, biodistribution characteristics, viral clearance, and immunogenicity of intratumoral administration of YH02 injection in patients with advanced solid tumors who have failed adequate standard therapy and lack effective treatment options, while preliminarily investigating its efficacy. No high-grade adverse drug reactions (ADRs) have been observed to date, nor were there any serious adverse events (SAEs), severe adverse drug reactions (SUSARs), or fatal events. The clinical safety and tolerability of this product for intratumoral administration are favorable.