Uncovering the anti-cancer mechanisms of Immuno-Oncology

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.

Epigenetic modulators such as HDACis have been developed for at least 20 years, and several drugs have been approved as targeted drugs worldwide. However, not every epigenetic modulator has immunoregulating activity. The GNTbm R&D team found that different structures of epigenetic modulators have different immunoregulating activities. Immunoregulation is very important and related to its anti-cancer activity, so development of a new drug with dual epigenetic and immunoregulating activities will be the key for cancer immunotherapy. 

The GNTbm R&D team has developed and designed epigenetic immunoactivators with novel structures, which was improved to enhance their epigenetic-modulating and immunoregulating activity through chemical structure optimization and computer simulation analysis, so as to achieve higher TME-regulating activity as shown in in vivo animal models. The new generation of epigenetic immunoactivator GNTbm-38, a small molecule oral drug candidate with benzamide-based structure, was screened by evaluating its anti-cancer activity with immunocompetent mice animal models. GNTbm-38 has been shown in multiple cancer-burdened immunocompetent mice to have excellent tumor immunoactivating activity, when combined with specific immunoregulating multi-kinase inhibitors, can fully activate and awaken the immune system by using very low dose. A very high ORR can be obtained, and in the re-challenge test, it is confirmed that it can produce lasting immune memory to prevent tumor recurrence.
 
The GNTbm-38 patent application has been completed in multiple countries worldwide, and has been approved in 36 countries. GNTbm-38 has completed preclinical research and will apply for IND in the United States, Taiwan, and China by the end of 2025. GNTbm-38 is one of the essential components of new generation cancer combination immunotherapy independently developed by GNTbm.

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.