ViroTher Targets 'Undruggable' Solid Tumors with First-in-Class Oncolytic Adenovirus Regulating Tumor Microenvironment Metabolism and Inflammation

A century ago, the theory that tumors originate from metabolic disturbances and chronic inflammation had already emerged.

In the mid-19th century, German pathologist Rudolf Virchow observed extensive infiltration of inflammatory cells in tumor tissues and proposed the hypothesis that tumors originate from chronic inflammation. In the early 20th century, Professor Otto Warburg discovered that even under conditions of sufficient oxygen, tumor cells tend to metabolize glucose into lactate via glycolysis. This finding, later known as the Warburg effect, ushered in the era of cancer metabolism research.

In recent years, with the advancement of metabolomics and the deepening of research on inflammation and cancer, the medical community has clearly established that uncontrollable inflammation (persistent chronic inflammation) is involved in every stage of tumorigenesis, including development, malignant transformation, invasion, metastasis, immune evasion, and cachexia. It is also closely related to the efficacy of anticancer therapies. Chronic inflammation can be triggered by biological, physical, and chemical factors, while metabolic disorders and psychological factors also contribute to its pathogenesis.

For instance, gastric cancer is associated with ulcerative inflammation caused by Helicobacter pylori infection; nasopharyngeal carcinoma, liver cancer, and cervical cancer are respectively linked to persistent chronic inflammation induced by Epstein-Barr virus (EBV), hepatitis viruses, and human papillomavirus (HPV) infections; whereas colorectal cancer is associated with colonic polyps (hyperplastic inflammation). Additionally, conditions such as obesity and depression contribute to tumorigenesis and progression by inducing systemic inflammation and metabolic disorders, and are closely correlated with therapeutic efficacy.

Therefore, how to eliminate chronic inflammation and correct metabolic disorders to enhance the efficacy of anti-tumor therapy and management of comorbidities remains a critical scientific question in the global field of oncology, potentially holding the key to breakthroughs in cancer treatment.

Nanjing ViroTher Biopharmaceutical Co., Ltd. (hereinafter referred to as “ViroTher”) focuses on tumor-promoting chronic inflammation and metabolic disorders (particularly lipid metabolism abnormalities), developing globally first-in-class recombinant oncolytic virus therapeutics that leverage the unique advantages of oncolytic viruses to eliminate tumor-promoting inflammation within the tumor microenvironment (TME) and correct lipid metabolism dysregulation. Its core pipeline product, Recombinant NV-A01 Adenovirus Injection, is currently in Phase I clinical trials for registration.VCBeat interviewed Professor Wei Jiwu, a doctoral supervisor in oncology at Nanjing University Medical School and the founder and general manager of ViroTher, to discuss how oncolytic viruses exert therapeutic effects in clinically refractory indications—such as triple-negative breast cancer, recurrent glioma, and advanced pancreatic cancer—by modulating inflammation and metabolism within the tumor microenvironment.

Wei Jiwu graduated from Huazhong University of Science and Technology with a degree in Clinical Medicine. He has eight years of clinical experience in general surgery and neurosurgery. He earned his Ph.D. from the Faculty of Medicine at Ulm University, Germany, and completed postdoctoral research at both Ulm University and the Faculty of Medicine at Ludwig Maximilian University of Munich, Germany. He later served as Professor of Oncology and Doctoral Supervisor at Nanjing University Medical School. With nearly two decades of expertise in oncolytic virus therapy, he focuses on the development of oncology drugs, including recombinant oncolytic viruses that modulate the tumor microenvironment involving inflammation, immunity, and metabolism. He has filed 15 invention patents related to oncolytic viruses.

Oncolytic Virus (OV), a class of natural or genetically engineered viruses that preferentially infect tumor cells and replicate rapidly within them, causes minimal damage to normal cells and exhibits a favorable safety profile. With multiple antitumor mechanisms—including oncolysis, induction of systemic antitumor immune responses, and efficient expression of recombinant proteins—oncolytic viruses serve as an excellent platform for the development of anticancer therapeutics.

Professor Wei Jiwu believes that oncolytic viruses can be broadly categorized into three types based on their mechanisms of action: those oriented toward enhancing oncolytic potency (such as Ankerui), those oriented toward immune activation (such as T-VEC), and those oriented toward correcting inflammatory and metabolic dysregulation in the solid tumor microenvironment. The majority of oncolytic viruses currently under development belong to the first two categories, whereas ViroTher’s product pipeline falls into the third category, with no similar products having entered clinical trials globally to date.

Professor Wei Jiwu stated, “Merely killing tumor cells (including through chemotherapy, radiotherapy, and immunotherapy) fails to improve the ‘soil’ that fosters malignant cells; otherwise, such treatment is merely a symptomatic measure akin to ‘cutting chives,’ where regrowth is inevitable. Effective treatment must target the root cause of the disease, addressing both symptoms and underlying causes simultaneously to achieve favorable long-term outcomes. Cancer is fundamentally a metabolic disorder and a non-resolving chronic inflammatory condition. Therefore, cancer therapy should address its source by improving the ‘soil’ that nurtures malignant cells, specifically by correcting lipid metabolism dysregulation within the tumor microenvironment (TME) and suppressing pro-tumorigenic inflammation.”

Lipid metabolism disorders and chronic inflammation often mutually reinforce each other. Inflammation acts as one of the “two sparks” that ignite lipid dysregulation, while lipids further fuel chronic inflammation. This interplay frequently contributes to the development of various major chronic diseases, such as cancer, obesity, atherosclerosis, neurodegenerative changes, and autoimmune diseases.

Therefore, the ViroTher team leverages specific proteins highly expressed by recombinant oncolytic viruses in the tumor microenvironment (TME) to correct lipid dysregulation and suppress pro-tumorigenic inflammation.Currently, the lead candidate in the pipeline, recombinant NV-A01 adenovirus injection, has entered Phase I clinical trials for indications including triple-negative breast cancer, advanced hepatocellular carcinoma, and other malignant solid tumors. Meanwhile, the team has completed the exploration of safety and clinically recommended dosing in patients with recurrent high-grade glioma and is currently conducting expanded-dose studies to evaluate clinical efficacy. In addition, recombinant VRT-G01 adenovirus injection, another globally innovative therapy that regulates fatty acid metabolism, has entered pilot-scale production, with a focus on advanced pancreatic cancer. Several other candidates in the reserve pipeline have completed preclinical studies on efficacy and related mechanisms.

It is reported that NV-A01, a recombinant human adenovirus type 5, is designed to correct cholesterol metabolism dysregulation in the tumor microenvironment and inhibit multiple inflammatory pathways.Wei Jiwu’s team has previously developed various oncolytic viruses, including measles virus, Newcastle disease virus, vaccinia virus, and adenovirus. ViroTher selected serotype 5 adenovirus primarily because this strain served as the backbone for China’s first approved oncolytic virus product (Ankerui), which was launched in 2005. This choice offers industrialization advantages such as a high safety profile, low regulatory risk, and well-established upstream and downstream manufacturing processes.

Based on the recombinant human adenovirus type 5 backbone, the ViroTher team inserted protein expression genes that regulate cholesterol and fatty acid metabolism.In vitro pharmacodynamic studies have demonstrated that NV-A01 induces robust expression and secretion of apolipoprotein A1 (ApoA1) following cellular infection. ApoA1 is the primary protein component of high-density lipoprotein (HDL), which plays a pivotal role in regulating reverse cholesterol transport and maintaining cellular cholesterol homeostasis. NV-A01 elicits significant cholesterol efflux in cells from multiple species, including humans, rhesus monkey kidney cells, mice, rats, and hamsters.

Professor Wei Jiwu likened the mechanism of action of NV-A01 to that of a “detergent” and a “firefighter” within the TME.ApoA1 generated by NV-A01 is a key component of high-density lipoprotein (HDL) in the human body. As an amphipathic molecule, it can bind to abnormally accumulated cholesterol in the tumor microenvironment (TME) interstitial fluid and transport it to the liver for metabolism. This process transforms the originally "lipid-rich" TME into a cleaner environment, facilitating immune cell infiltration, while significantly reducing the tumor cells' capabilities for invasion, metastasis, and immune evasion. Meanwhile, ApoA1 induces targeted "slimming" of tumor-associated macrophages, enhancing their phagocytic capacity against tumor cells and activating anti-tumor immunity. Additionally, ApoA1 acts as a "firefighter" to extinguish the "two fires" in the TME—namely inflammation, particularly pro-tumorigenic inflammatory pathways such as NF-κB and STAT3.

Dysregulated cholesterol metabolism is a hallmark of various cancers, including glioblastoma, colorectal cancer, and breast cancer. Based on this, the indications for NV-A01 include glioma, triple-negative breast cancer, liver cancer, and certain tumors associated with cholesterol dysregulation.

In China, the annual incidence of gliomas is approximately 96,000 cases, among which the annual incidence of grade 4 glioblastoma (as classified by the WHO) is about 60,000 cases, with a median overall survival of less than one year. The recurrence rate in patients with glioblastoma multiforme (GBM) approaches 100%. Once recurrence occurs, the disease course deteriorates rapidly, and survival typically does not exceed six months. This imposes significant suffering and economic burdens on patients, families, and society, while also presenting substantial challenges to clinical treatment.

On July 20, a research team led by Wei Jiwu from Nanjing University published a study in Nature Communications. The study provides insights into the mechanism by which dysregulated cholesterol metabolism in glioblastoma (GBM) impairs tumor-associated macrophage (TAM)/CD8+ T cell axis-mediated anti-tumor immunity, and on this basis, the team developed an ApoA1-armed recombinant oncolytic adenovirus (NV-A01). Preclinical results demonstrated that NV-A01 significantly restored anti-tumor immunity and established specific long-term immune surveillance in orthotopic glioma models across multiple species.

A clinical study of NV-A01 in patients with recurrent high-grade glioma, led by Professor Jiang Xiaochun and Director Shen Jie from Yijishan Hospital of Wannan Medical College, marks the first global clinical trial for glioma based on modulating cholesterol metabolism. Data from the dose-escalation study demonstrate that NV-A01 exhibits a favorable safety profile via intracranial tumor injection. Among the two subjects currently available for efficacy evaluation, imaging assessments indicate promising therapeutic effects: follow-up contrast-enhanced MRI scans at 6–8 months post-treatment showed no tumor progression, and the patients remain in good condition. Enrollment is ongoing for the expanded dose cohort of patients with recurrent high-grade glioma.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounting for approximately 12%–17% of all breast cancer cases. Due to the lack of well-defined, actionable therapeutic targets, progress in developing effective pharmacological treatments has been slow. Owing to its high heterogeneity, poor differentiation, strong invasiveness, and propensity for earlier and more frequent metastasis, TNBC is generally associated with a poor prognosis, with a 5-year survival rate of less than 15% and a median overall survival of only 13 months.

Epidemiological and large-scale gene sequencing studies have shown that with the increasing prevalence of obesity, hyperglycemia, and hyperlipidemia, metabolic disorders have become widespread, leading to an increased incidence of triple-negative breast cancer (TNBC). Potential metabolic abnormalities that promote TNBC progression include elevated levels of total cholesterol, circulating low-density lipoprotein cholesterol (LDL-C), triglycerides, and insulin, as well as decreased levels of high-density lipoprotein cholesterol (HDL-C).

On April 3, a research paper was published online in the Journal of Experimental & Clinical Cancer Research, with Wei Jiwu and Yang Fuming from Nanjing University and Zuo Shuguang from Guangxi Medical University serving as co-corresponding authors. The study elucidated the role and mechanism of cholesterol in the progression and metastasis of triple-negative breast cancer (TNBC). It reported for the first time that ApoA1 significantly reduces TNBC invasion and metastasis by inhibiting the cholesterol/lipid raft/IKK/FOXO3a/KRT14 axis, and demonstrated favorable safety and tolerability in both rhesus monkeys and Syrian hamsters.

In the interview, Professor Wei Jiwu noted that non-replicating adenoviruses were the earliest expression vectors to enter the field of gene therapy. Looking back at the historical development of oncolytic viruses, it is evident that the mainstream developmental trajectory has focused on killing tumor cells, progressing from enhancing oncolytic efficacy (through replicative strains with faster replication rates) to expressing immune-activating factors (via insertion and genetic engineering).ViroTher’s core philosophy is not to maximize the oncolytic killing of cancer cells by the virus, but rather to utilize the virus as a vector for highly efficient expression within the tumor microenvironment. Under this paradigm, ViroTher is developing an oncolytic virus product grounded in gene therapy principles that organically integrates metabolism, inflammation, and immunity.

Professor Wei Jiwu emphasized, “Unless lipid metabolism disorders in solid tumors are corrected and chronic inflammation is suppressed, the efficacy of all treatments will be compromised. Our oncolytic virus product precisely targets these two fundamental aspects. The proteins expressed by the recombinant virus serve a dual function as both a lipid-lowering ‘detergent’ and an anti-inflammatory ‘firefighter,’ effectively remodeling the microenvironment that fosters malignant transformation. As the microenvironment improves, tumor cells become less aggressive. More importantly, immune cells recruited into the tumor microenvironment by the oncolytic virus no longer ‘aid the malignancy,’ but instead faithfully perform their immune surveillance functions.”

Currently, ViroTher has obtained five Chinese invention patents, one U.S. invention patent, and one Japanese patent authorization, with multiple PCT and European Union invention patent applications pending. As clinical work progresses steadily, ViroTher has launched a new round of financing and is seeking partners to expedite the advancement of NV-A01 into pivotal clinical trials for glioma, initiate phased clinical studies of VRT-G01 for pancreatic cancer, and leverage fast-track pathways such as the “Breakthrough Therapy” designation to benefit patients with urgent unmet clinical needs at an earlier stage.

From a broader perspective, research and development targeting solid tumor-associated metabolic disorders, chronic inflammation, and the tumor microenvironment is flourishing globally. JAK inhibitors, which can target chronic immune regulatory functions that contribute to relapse during cancer immunotherapy, represent a promising strategy warranting further preclinical and clinical investigation.For example, in June this year, *Science* simultaneously published two studies involving JAK inhibitors, highlighting the immense potential of immune modulation in cancer therapy. One of these studies focused on the inflammatory mechanisms of tumors and designed a combination regimen of JAK inhibitors plus PD-1 inhibitors, achieving a median progression-free survival (PFS) of 23.5 months in the treatment of non-small cell lung cancer (NSCLC).

Professor Wei Jiwu’s team and ViroTher are also exploring additional solid tumor indications with urgent clinical needs and no effective treatments, including recombinant VRT-SS01 adenovirus for malignant pleural and ascitic effusions in patients with advanced solid tumors, VRT-TP01 for metastatic colorectal cancer, and VRT-LG01 for recurrent renal cell carcinoma and metastatic cancers. Furthermore, for patients whose cancer has progressed to cachexia, the team aims to develop novel therapeutics targeting inflammation and metabolism to improve both quality of life and survival time.