In the crowded field of tumor immunotherapy, most companies focus on developing targeted drugs around keywords such as T cells, PD-1, and CAR-T. But what if a patient does not have the target?

“I’ve asked many companies developing targeted drugs, and none could answer this question,” Zhou recalls. During his years in New York investing in biotech, he encountered numerous innovative drug companies, almost all telling the same story: find a target, develop the targeted drug, and precisely attack tumors. “Targeted drugs are like missiles; tumor antigen targets serving as GPS coordinates.”

This logic is theoretically perfect—but has a fundamental flaw in practice: not all tumor patients have usable targets. Even when targets exist, the abundance and heterogeneity of tumor targets make it difficult for single-target drugs to completely eliminate all cancer cells in tumor tissue. After patient receiving treatment, target-positive cells are killed, while target-negative cells survived, often leading patient to drug resistance or recurrence, eventually leaving no treatment options.

Faced with this dilemma, Zhou's solution is simple but bold:  if tumor cells lack targets, then install targets onto them; if in vitro produced drugs cannot efficiently reach tumors, then make tumor cells produce anti-tumor drugs themselves in vivo.

“Based on the First Principle Thinking, problems should be solved from the most fundamental proposition: directly targeting tumors.”

In 2018, Zhou founded Joint Biosciences in the U.S., and in 2020 established Joint Biosciences (SH) Ltd. in Shanghai to pursue direct tumor cell reprogramming.

Today, the OVV-01 therapy developed based on this concept has entered Phase II clinical trials in both the U.S. and China, and has obtained fast-track approval from the US FDA and China NMPA. There is no benchmark company for clinical trials worldwide.

The foundation of OVV-01 is a modified vesicular stomatitis virus (VSV) vector developed by Joint Biosciences over many years, forming its key technological barrier.

VSV naturally targets tumor cells. In normal cells, it is suppressed by the type I interferon pathway and cannot replicate. In tumor cells, where this pathway is defective, the virus replicates efficiently—up to over 1,000-fold amplification. It poses minimal risk to humans, causing only mild, non-lethal symptoms like oral blisters in pigs, cattle, and horses.

Starting from 2017, the R&D team spent a full three years to improve the stability of this RNA virus to a usable level. RNA viruses are naturally prone to mutations, and their structure must be stabilized in order to insert foreign genes. After countless failures, they ultimately achieved stability far beyond the FDA standard requirements.

Using this platform, Joint Biosciences built a unique in vivo dual-delivery system: “In Vivo Antigen Targets + In Vivo Bispecific/Tri-specific/Multi-specific Antibodies.” Tumor cells are engineered to produce both antigen targets and therapeutic antibodies, enabling tumor cells self-destruction.

Artificial tumor antigens are precisely positioned on tumor cell membranes, making them recognizable to the immune system. Meanwhile, genes encoding multi-specific antibodies are delivered into the tumor cells. Once inside, tumor cells produce antibodies that recognize and attack their own antigens—creating a “self-consuming” killing mechanism.

“The tumor cell is the factory; the antibodies it produces destroy it locally,” Zhou explains with a vivid analogy.

Additionally, tumor tissues contain heterogeneous cells at different stages. Traditional therapies act like single-stage, single-target missiles. Zhou’s approach deploys multiple “missiles” across stages and targets, leaving cancer cells nowhere to hide.

The significance of this technology platform lies not only in its innovative mechanism of action but also in completely circumventing the classic dilemma of tumor treatment. Since both antigens and antibodies are delivered at the same time by the same viral vector, doctors don’t need to screen patients for specific targets before treatment. Any tumor patient, regardless of tumor type, stage, or target expression status, can receive this treatment.

Genetically engineered OVV-01 selectively replicates in tumor cells, lyses them without harming normal cells, and acts as a therapeutic vaccine—activating T cells and preventing metastasis and recurrence, forming a “lysis–sensitization–killing” loop for long-term control.

Traditional oncolytic viruses are injected directly into tumors. Joint Biosciences pioneered a combined intratumoral + intravenous delivery approach—the only virus-based oncology therapy globally approved by both the FDA and China CDE for such use.

This innovation in drug administration enables comprehensive, “no blind spot” coverage of tumors throughout the body.

Zhou explains that tumor location reflects systemic imbalance of a whole body, not only immune system. Different administration routes activate different physiological systems of the body, including the immune system. Only combined approaches can mobilize full-body anti-cancer defenses.

The team has expanded to 11 delivery methods, including intratumoral, intravenous, subcutaneous, intramuscular, intracranial, intrathecal, intraperitoneal, and bladder instillation etc. Physicians can tailor delivery to tumor location while stimulating multiple systems for a coordinated anti-cancer response.

Zhou’s journey began with personal loss. During his PhD study stage, his cousin was diagnosed with liver cancer and died within two weeks.

“That impact was profound. I vowed to develop new cancer therapies and find breakthroughs.”

Tears welled up in his's eyes, brimming with warmth and sentiment. His interdisciplinary background fueled innovation.  

In the 1990s, he pioneered transferring antibacterial peptide genes from animals into plants. he was the first to break the boundaries between animal and plant genes, completing the first research on transferring animal peptide genes resistant to drug-resistant bacteria into plants for production, with results published in top-tier journals.   

Thereafter, his research directions continued to expand, covering multiple biotechnology fields. He developed eye drops for drug-resistant bacteria, transferring specific genes to achieve antibacterial functions; he also attempted to apply them in anti-infection fields. In the 1990s, he also combined heat shock proteins with HPV antigens to develop therapeutic cervical cancer vaccines for immunotherapy, founding his first company and sold it.

His experience in new drug investment in New York from 2014 to 2019 exposed real-world gaps in drug development. During that time, he visited hundreds of American tumor innovative drug R&D companies, finding that all were focusing on tumor targeted drugs without exception. He observed that no company could answer: what about patients without targets?

This observation prompted him to rethink the field: For patients without targetable sites, are there blind spots in existing drug development.

In 2017, Zhou officially launched the development of this new technological direction in the United States, and the innovation journey of Joint Biosciences began.

Today, OVV-01 has cleared Phase I to Phase II clinical trial, becoming the world's first company to advance "antigen target loading on tumor cells", with approvals for 9 solid tumor indications, covering common tumors such as non-small cell lung cancer and colorectal cancer, as well as various rare small tumors. It has not only received Fast Track designation from China's CDE and the US FDA but has also been exempted from Phase I clinical trials by both agencies, with Phase II clinical trials underway in both China and the United States.

Meanwhile, Joint Biosciences has established multiple investigator-initiated Trials (IIT) for clinical collaborations with top-tier oncology hospitals in the United States and China, developing life-saving drugs for patients.

In the early days of entrepreneurship, when introducing the project to investors, Zhou was often asked an awkward question: "Who is the US benchmark company for your project?" He admitted that this question once posed considerable challenges during the fundraising process.

Since no companies worldwide were pursuing the same technical approach, investors often struggled to assess the project's technical value and market prospects. According to his observation, approximately 90% of funds showed hesitation during initial contact.

Only in recent years have a few US companies emerged with similar concepts—using viruses to express tumor antigens combined with cell therapies like CAR-T. However, these companies' technologies remain in preclinical stages, whereas Joint Biosciences' technology platform in Phase II trials leads by at least five years in progress.

In the domestic market, although numerous players exist in the tumor immunotherapy track, nearly all focus on mainstream technical directions such as CAR-T, PD-1, and ADC. The "tumor cell modification" path pioneered by Joint Biosciences currently has no followers.

From a technical barrier perspective, this approach involves multiple critical components: screening and stabilization modification of viral vectors, efficient loading and expression of exogenous genes, design and screening of multi-target antibodies, and clinical validation of various administration methods. Each component requires long-term technical accumulation and extensive experimental data support. Even if other companies choose to follow, it would take years to establish corresponding technical capabilities.

Today, multiple US and international pharmaceutical companies have proactively extended cooperation offers to Joint Biosciences, hoping to collaborate on “installing” tumor target loading. "US companies come to us for target loading. I'm currently in discussions with them. Breakthrough first, then consider major licensing later," Zhou stated.

Zhou is not concerned about imitators. He believes that a technical track needs sufficient participants to attract continuous capital and talent inflow, thereby driving the entire field forward. "A single tree cannot make a forest." He hopes more companies will join this direction in the future, collectively expanding the track.

Currently, Joint Biosciences has established deep collaborations with several leading domestic pharmaceutical companies, including Akeso Biopharma. Meanwhile, the company is further advancing its global patent layout, with core technologies already granted multiple international and domestic patents.

 In Vivo CAR-Tumor, New Direction of Immune Cell Therapy．Dr. RuiRong Yuan's Comments On: An Interview with Dr. George Zhou, the Inventor, Founder and CEO of Joint Biosciences

Most current immunotherapy strategies rely on identifying tumor-specific targets. However, not all tumors express actionable targets, and even when present, tumor heterogeneity often limits therapeutic durability.

Dr. Zhou recalls his observations during his years in biotechnology investment:

“Many development strategies follow a similar paradigm—identify a target and design a therapy against it. Yet, a critical question remains insufficiently addressed: what options exist for patients without targetable features?”

To address this limitation, Joint Biosciences has explored an alternative strategy:

• Introducing synthetic antigen targets directly into tumor cells 

• Enabling tumor-localized production of therapeutic agents 

This approach reflects a first-principles perspective—focusing directly on tumor cells as the central therapeutic target.

Founded in 2018 in the United States, Joint Biosciences has advanced this concept into clinical development. The lead program, OVV-01, is currently under Phase II evaluation in both the United States and China, with regulatory fast-track designations.

The OVV-01 platform is based on a modified vesicular stomatitis virus (VSV) vector.

Key biological features include:

• High intratumoral amplification capacity 

Following extensive engineering to improve genomic stability, this RNA virus platform enables a dual-delivery system:

His design creates a localized therapeutic mechanism:

“In this system, tumor cells function as localized production units, generating therapeutic molecules that act directly within the tumor microenvironment,” Zhou explains.

Importantly, this strategy may reduce dependence on pre-existing target expression and potentially address tumor heterogeneity through multi-target engagement.

Traditional oncolytic virus therapies are typically administered via intratumoral injection. In contrast, this platform incorporates combined delivery approaches, including:Intratumoral 、Intravenous 、Subcutaneous 、Intramuscular、Thoracic、Abdominal、Pelvic、Intracranial 、Intrathecal、Bladder Instillation、Inhalation、administration

Additional routes depending on tumor location 

This multi-route strategy is designed to:

Dr. Zhou’s scientific trajectory spans molecular biology, translational research, and biotechnology innovation.

His early work included:

• Exploration of therapeutic cancer vaccines 

Subsequent experience in biotechnology investment provided insights into the limitations of prevailing drug development paradigms—particularly the reliance on predefined targets.

These observations led to the initiation of the current platform in 2017.

The OVV-01 program has since progressed to Phase II clinical studies across multiple solid tumor indications, including both common and rare cancers. Phase II trial and Collaborative investigator-initiated trials are ongoing in the United States and China.

The “tumor cell reprogramming” strategy represents a relatively underexplored direction in oncology.

While emerging approaches in the United States have begun investigating related concepts—such as viral delivery of tumor antigens combined with cell therapies—most remain at preclinical stages.

The platform of Joint Biosciences integrates several technically demanding components:

• Optimization of delivery strategies 

Each of these elements requires substantial experimental validation and technical integration.

The company has established collaborations with multiple academic and industry partners and continues to expand its global intellectual property portfolio.

A central premise of this approach is to reconsider the direction of engineering in immunotherapy.

Conventional CAR-T cell therapy focuses on modifying immune cells to recognize tumor targets. In contrast, this platform explores modifying tumor cells to enhance immune recognition.

“Rather than exclusively engineering immune cells, we asked whether tumor cells themselves could be modified to improve visibility to the immune system,” Zhou notes.

This concept aims to address a fundamental challenge in oncology:

• Enhance endogenous anti-tumor responses 

The development of in vivo CAR-Tumor represents an exploratory but potentially impactful new field and new direction in cancer therapy. If validated clinically, the new platforms based on tumor-targeted gene delivery and in situ therapeutic production may:

• Expand treatment options for patients lacking targetable biomarkers

• Complement existing immunotherapy modalities

• Contribute to a broader conceptual framework for tumor-directed engineering

   

                                                                                         Dr. RuiRong Yuan Bio

Dr. RuiRong Yuan is a U.S. board-certified medical oncologist, physician-scientist, and senior biopharmaceutical executive, with over 30 years of experience spanning clinical medicine, academic research, and global oncology drug development. She currently serves as an attending physician in Hematology and Oncology at the VA Medical Center affiliated with Rutgers New Jersey Medical School, and as a scientific advisor to several international biotechnology companies. She is also the Editor-in-Chief of Cancer Care: Insights & Stories .

Dr. Yuan previously served as Director of the Immunology Research Laboratory at New Jersey Medical School, where she led translational research in tumor and neuroimmunology, with several findings advancing into early clinical development. She subsequently held senior executive roles at multinational pharmaceutical companies, including Novartis, Daiichi Sankyo, BeiGene, and Eisai, serving in positions such as President and Chief Medical Officer, where she led the development, regulatory approval, and global commercialization of multiple anticancer therapies.

She is a founding Board Member of the Chinese American Hematologist and Oncologist Network (CAHON), where she previously served as President and Chair of the Board, and also served on the International Affairs Committee of the American Society of Clinical Oncology (ASCO). In addition to her medical career, Dr. Yuan is an active bilingual author, with multiple published works of fiction and poetry in both English and Chinese.