Uncovering the anti-cancer mechanisms of Immuno-Oncology

Tumor Microenvironment Regulators (TMRs) screening platform GNTbm-38 GNTbm-TKI

Cancer Immunotherapy

Cancer Immunotherapy represents a paradigm shift in modern oncology. The resilience of cancer cells stems from their sophisticated "disguise"—the expression of specific proteins that deceive immune cells, misleading the immune system into recognizing them as normal tissue and allowing them to evade host surveillance.

Unlike conventional chemotherapy or radiotherapy, which rely on direct cytotoxicity, the core logic of immunotherapy is to reactivate or bolster the patient's endogenous immune system, empowering the "immune army" to identify and eradicate malignant cells. Currently, three primary therapeutic modalities dominate the landscape: Immune Checkpoint Inhibitors (ICIs), CAR-T cell therapy, and Tumor Microenvironment (TME) modulators.

The central concept of these three approaches is the precise regulation of distinct immune phenotypes, ensuring therapeutic efficacy for both "hot" (inflamed) and "cold" (non-inflamed/immune-excluded) tumors. "Hot" tumorsare characterized by a pre-existing infiltration of T-cells that have been rendered dysfunctional by inhibitory signals, such as checkpoint molecules or immunosuppressive cell populations. Conversely, "cold" tumors exhibit a profound lack of T-cell infiltration, typically due to an exclusionary microenvironment that prevents the immune system from recognizing or initiating an anti-tumor response.

Consequently, different immunotherapeutic strategies are employed: Immune Checkpoint Inhibitors primarily function by "releasing the brakes" on T-cells, re-engaging an existing but suppressed immune response; CAR-T cell therapyinvolves genetically engineering a patient’s T-cells to enhance their precision in recognizing and attacking cancer cells; and TME modulation focuses on remodeling the tumor’s surrounding environment to facilitate immune cell entry. The latter is capable of transforming a "cold" tumor into an "active" state, thereby significantly enhancing the overall therapeutic window.

Tumor Microenvironment Remodeling screening platform

Cancer immunotherapy has become the most promising area with novel mechanisms for the treatment of advanced cancer, mainly by reactivating the patient's immune system, correcting the mechanism of immune escape that had occurred, and releasing the activity of CTLs to attack tumors and generate immune memory.

After 10 years of development, cancer immunotherapy, mainly focused on ICIs, has entered a new generation of cancer immunotherapy. The new approach considers the need of remodeling TME, primarily using anti-PD-1/VEGF or anti-PD-L1/VEGF bispecific antibody (BSA). Although BSAs are regarded as superior to monoclonal antibodies in terms of the efficacy, their ability to enhance anti-angiogenesis is limited, and they do not truly address the challenges in treating cold tumors. The benefits of BSAs in cancer immunotherapy still do not meet the treatment needs of patients with cold tumors. Therefore, it is necessary to combine with other drug X to enhance the remodeling of the TME and achieve better outcomes in cancer immunotherapy.

A new generation of epigenetic immunoactivator screening platform

Epigenetics refers to heritable changes in gene expression that occur without altering the underlying DNA sequence. In the context of oncology, epigenetic immunoactivators function by modifying epigenetic marks on cancer cells to "unmask" previously evaded malignant cells. By reactivating suppressed immune responses and empowering T-cells to execute their anti-tumor functions, this approach serves as a viable alternative to conventional chemotherapy, aiming to achieve therapeutic efficacy while minimizing systemic toxicity.

While epigenetic modulators such as HDAC inhibitors (HDACi)—a class of targeted therapies—have been under development for over 20 years with multiple globally approved drugs, not all modulators possess immunoregulatory activity (the capacity to modulate, alter, or remodel immune responses). The R&D team at GNT Biotech Hub (GNTbm)has identified that varying chemical structures lead to distinct immunoregulatory profiles. Given that immune modulation is intrinsically linked to anti-cancer potency in immunotherapy, the dual possession of epigenetic and immunoregulatory activities is critical for next-generation drug development.

Leveraging a proprietary, de novo design approach, GNTbm has developed a next-generation epigenetic immunoactivator. Through structural optimization and computational modeling, the team has enhanced both its epigenetic regulatory potency and immunoregulatory activity to achieve superior tumor microenvironment (TME)modulation. Utilizing GNTbm’s established animal testing platforms, GNTbm-38 was identified as a lead candidate—a next-generation small molecule benzamide with a novel chemical structure.

In multiple immunocompetent animal models with high tumor burden, oral administration of GNTbm-38 demonstrated exceptional immunoregulatory activity. When combined with specific immunomodulatory multi-kinase inhibitors, GNTbm-38 completely activated the immune system at significantly lower doses, yielding a remarkably high Objective Response Rate (ORR). Furthermore, re-challenge studies have confirmed the induction of durable immunological memory, effectively preventing tumor recurrence.

To date, GNTbm-38 has filed for global patent protection across multiple jurisdictions, with approvals granted in 36 countries. Having completed its preclinical studies, GNTbm-38 filed Investigational New Drug (IND) applications in the United States, Taiwan, and China by the end of 2025. GNTbm-38 stands as a cornerstone therapy in GNTbm’s proprietary pipeline for oral cancer immunotherapy.

Immunoregulating multi-kinase inhibitor screening platform

Tyrosine Kinase Inhibitors (TKI) are a well-known class of anti-cancer drugs and a lot of them have been approved for marketing worldwide. GNTbm's R&D team has shown that a specific type of TKIs has strong immunoregulating activity, which is conducive to controlling the TME, when combined with GNTbm-38, can activate and awaken the host immune system by remodeling the TME, which will lead to significant anti-cancer activity, long-term immune memory, and long-lasting remission without tumor recurrence, in so-called cancer immunotherapy.

In the absence of immune checkpoint inhibitors, drug combination in cancer immunotherapy refer to combination of drugs with unique TME-regulating mechanisms to remodel the TME, including normalization of tumor blood vessels, alleviation of the hypoxia state, reduction of lactic acid accumulation, infiltration of a large number of CTLs to recognize and attack cancer cells, inhibition of infiltration of immunosuppressive cells (such as TAMs, MDSCs, and Tregs), and regulation of cytokines and chemokine gene expression in the TME. The cancer immunotherapy developed by GNTbm will be “GNTbm-38+Y”, in which Y can be a known TKI or to achieve a even more effective outcome when Y is GNTbm-TKI, independently developed by GNTbm, in the goal of reaching the best therapeutic benefits.

After years of research, the R&D team at GNTbm has independently developed a novel TKI with a new chemical entity that inhibits unique targets (TYRO3, AXL, c-MER, BTK, ROS1, NTRK2, MET, VEGFR2). This multi-kinase inhibitor, GNTbm-TKI, exhibits strong immune regulation activity. Animal tests have also confirmed that GNTbm-TKI, in combination with GNTbm-38, achieved over 80% ORR in anti-cancer activity and generated immune memory, lasting suppression of tumor relapse. The R&D team is conducting further research on animal tests.

The multi-kinase inhibitor candidate GNTbm-TKI, which has strong immune regulation activity, has been completed patent applications in multiple countries worldwide and has entered preclinical research. It is expected to complete IND applications in the United States, Taiwan, and China by the end of 2026.

The mechanisms of GNTbm-TKI in inhibiting cancer cell growth/invasion and metastasis/tumor angiogenesis and remodeling tumor microenvironment