Sun Yat-sen University to Transfer Hepatocellular Carcinoma Immunotherapy Patent for RMB 500,000

Recently, Sun Yat-sen University and the Sun Yat-sen University Cancer Center (Sun Yat-sen University Affiliated Cancer Hospital, Sun Yat-sen University Cancer Research Institute) announced an invention patent in the field of liver cancer treatment—“Application of BMP9 in Combination with NK Cells and PD-L1 Antibodies in the Preparation of Drugs for Liver Cancer”Public Notice on the Transformation of Scientific and Technological Achievements. The university intends to transfer the patent right at500,000 yuantransferred to the industry party at a price in RMB. The inventor of this patent isXiang Tong, Xia Jianchuan, Han Yulongcomposed of et al.

This patent specifically relates toA technology for the combined application of bone morphogenetic protein 9 (BMP9), natural killer cells (NK cells), and programmed death-ligand 1 (PD-L1) antibodies in the preparation of therapeutic agents for liver cancer,This approach aims to improve the efficacy of immunotherapy for hepatocellular carcinoma (HCC), particularly in hepatitis B virus (HBV)-positive HCC. By introducing BMP9, this technology significantly increases the accumulation and activation levels of natural killer (NK) cells within tumor tissues, thereby enhancing the inhibitory effect of combination therapy on tumor growth and addressing the limitations of single-agent PD-L1 antibody therapy in terms of clinical response rates.

Primary Hepatocellular Carcinoma (HCC)It is the sixth most common cancer type globally and the third leading cause of cancer-related deaths. Particularly in China, the majority of liver cancer cases are closely associated with hepatitis B virus (HBV) infection. Although some patients with early-stage disease can be cured through surgical resection, liver transplantation, or ablation techniques, liver cancer often has an insidious onset. Consequently, the vast majority of patients are diagnosed at intermediate or advanced stages, having lost the opportunity for surgical intervention and facing a generally poor prognosis. Therefore, there is a significant clinical demand for systemic pharmacological treatments.

In recent years, with the advent of immune checkpoint inhibitors, the treatment of liver cancer has entered a new era of immunotherapy. Among them,PD-L1 Antibody Therapyhas become a critical component of first-line therapy. PD-L1 is a transmembrane protein widely expressed on the surface of tumor cells. By binding to the PD-1 receptor on T cells, it transmits inhibitory signals to the immune system, effectively applying the “brakes” to cytotoxic T cells and thereby helping tumor cells evade immune surveillance. The clinical use of PD-L1 antibodies aims to block this signaling pathway and reinvigorate the immune system’s ability to attack tumors. Although the FDA has approved PD-L1 antibodies for the treatment of unresectable hepatocellular carcinoma, and the therapy is generally manageable in terms of safety, the real-world clinical landscape remains challenging: data from numerous Phase III clinical trials show that the objective response rate (ORR) for PD-L1 antibody monotherapy is onlyApproximately 20%, which means that approximately 80% of patients cannot derive significant benefit from it.

The underlying cause of this dilemma lies inThe Complexity of the Tumor Microenvironment. Scientific research has found that simply releasing the “brakes” on T cells is not sufficient to trigger an effective immune response; T cells also need to be accurately “guided” to the tumor site. This process is highly dependent onA Special Type of Stimulatory Dendritic Cells (SDCs), while the accumulation and survival of SDCs within tumors are directly controlled by NK cells. The tumor microenvironment in many patients with liver cancer is characterized as an "immune desert," lacking sufficient active NK cells, which leads to inadequate recruitment of SDCs and ultimately causes T cells to become "lost" or unable to effectively recognize cancer cells. Consequently, therapeutic strategies relying solely on PD-L1 antibodies often fail due to the absence of this critical cellular interaction cascade.

To overcome this bottleneck, the focus of clinical development has shifted from monotherapy to combination therapy, particularly exploring how to introduce and activate NK cells to synergistically enhance the efficacy of PD-L1 antibodies. Previous clinical explorations in fields such as non-small cell lung cancer have confirmed that combining NK cells with PD-1/PD-L1 antibodies can nearly double the objective response rate. However, in liver cancer, especially HBV-positive liver cancer, how to more efficiently activate infused NK cells, enabling them to engraft within the tumor and sustain their function in recruiting SDCs, remains a key technical challenge limiting further breakthroughs in therapeutic efficacy.

In response to the aforementioned clinical challenges of immunotherapy in the field of liver cancer, a research team from Sun Yat-sen University has proposed a groundbreaking solution:Develop a Tripartite Combination Therapy Strategy of “BMP9 Protein + NK Cells + PD-L1 Antibody”This invention does not stop at the simple superposition of drugs, but keenly capturesBMP9InReshaping the Tumor Immune Microenvironmentkey role in, particularly with regard toHBV-Positive Hepatocellular Carcinoma Patients, this regimen provides a potent mechanism of immune sensitization.

The research team found that while the infusion of NK cells alone can increase the number of immune cells, these “warriors” often lack sufficient cytotoxic activity within the complex tumor microenvironment. The introduction of BMP9 precisely addresses this core challenge. According to experimental data presented in the patent specification,BMP9 significantly enhances the expression level of CD69 molecules on the surface of NK cells within tumor tissues.CD69 is a key marker of early lymphocyte activation; its upregulated expression signifies that NK cells have switched from a "quiescent state" to a highly active "combat state," substantially enhancing their ability to recognize and lyse tumor cells. Meanwhile, BMP9 also promotes the effective infiltration and accumulation of NK cells within the tumor microenvironment.

To ensure that this critical protein can precisely reach its target and exert its therapeutic effect, the patent also incorporates ingenious technical innovations in the method of administration. The invention team has developed aDrug-loaded Contrast Microbubbles（MB-BMP9）, which is a specialized carrier composed of a lipid bilayer encapsulating bioinert gas (perfluoropropane) and BMP9 protein. During treatment, throughUltrasound Cavitation TechnologyThese microbubbles can be directionally "detonated" at the tumor site, thereby achieving targeted release of BMP9. This targeted delivery system not only increases the local concentration of the drug within the tumor but also effectively avoids the side effects associated with systemic administration. Experiments have confirmed that this regimen significantly outperforms the control group without BMP9 in inhibiting tumor growth, providing robust technical support for overcoming the resistance bottleneck of PD-L1 antibody therapy in clinical practice.

The field of conversion therapy for liver cancer is currently characterized by a competitive landscape with multiple parallel treatment regimens.Atezolizumab Combined with BevacizumabIt is currently the first-line standard of care. Atezolizumab restores T-cell activity by blocking the PD-L1 pathway, while bevacizumab improves tumor vascular distribution by targeting VEGF, thereby alleviating immunosuppression in the microenvironment. Together, they have ushered in a new chapter in conversion therapy.

Camrelizumab Combined with ApatinibIt potently disrupts tumor blood supply and activates infiltrating lymphocytes through deep inhibition of the VEGFR-2 pathway and PD-1 antagonism, demonstrating excellent performance in studies involving Chinese patients with liver cancer.

Additionally,Lenvatinib in Combination with PembrolizumabThe regimen has also garnered widespread attention. As a multi-kinase inhibitor, lenvatinib simultaneously targets VEGFR and FGFR, offering multi-target advantages in inducing tumor shrinkage and downregulating immunosuppressive cells (such as MDSCs).

In recent years,Triple Therapy (e.g., TACE or HAIC combined with targeted therapy and immunotherapy)It has become a focal point, with its core logic involving the induction of tumor necrosis and substantial release of tumor antigens through local embolization or perfusion, combined with systemic immunotherapeutic agents to further amplify the anti-tumor effect. Despite the continuous evolution of these competing products, the complexity of the immune microenvironment still results in suboptimal responses in some patients. The “BMP9 combined with NK cells and PD-L1 antibody” regimen proposed in this project pioneers a new pathway—“precise activation of NK cells by BMP9 plus targeted drug delivery via drug-loaded microbubbles”—going beyond the systemic immunity relied upon by most existing competitors.