Uncovering the anti-cancer mechanisms of Immuno-Oncology

Tumor Microenvironment Regulators (TMRs) screening platform Tumor Microenvironment Regulators (TMRs)

In the development of anti-cancer drugs there are hundreds of drugs that are covered in dozens of anti-cancer mechanisms. But there are very big differences, some anti-cancer mechanisms are quite common and some are very powerful. Cancer immunotherapy are classified as the latter with many anti-cancer benefits. Cancer immunotherapy is to reactivate or awaken the patient‘s immune system, therefore restores the ability of immune system to attack the tumor, and produces immune memory so that the tumor is not easy to recur. This mechanism does not rely on drugs direct killing of cancer cells. In cancer immunotherapy, tumor microenvironment regulators have the most potential for inducing excellent tumor response.
The differences between TMRs and immune checkpoint inhibitors (ICIs) are as follows:

GNTbm has constructed a reliable animal platform for screening TMRs, and has successfully developed three TMRs: GNTbm-CC-01 (CC-01), GNTbm-CC-02 and GNTbm-CT-01 (CT-01)

In in vivo animal models, these oral TMRs activate the body’s immune system mainly through mechanisms including increase of antigen presentation, normalization of tumor blood vessels, alleviation of the hypoxia state of the tumor microenvironment, reduction of lactic acid accumulation, so that a large number of CTLs with the ability to identify and attack cancer cells are attracted and infiltrate into the tumor microenvironment to attack the tumor. TMRs will also inhibit the number of immunosuppressive cells (such as TAMs, MDSCs, and Tregs) in the tumor microenvironment, which are conducive to the CTLs for attacking the tumor. The tumor growth is significantly inhibited, and immune memory is generated in the body, providing long-lasting remission benefits. Therefore, even after stopping treatment with these TMRs, the body still remains the ability of inhibiting tumor growth, by showing a good ORR (Objective response rate) in the treated group. TMRs possess a more comprehensive anti-cancer mechanism, which is very different from that of immune checkpoint inhibitors, that is, the activation of CTL, and is a more robust and effective next-generation cancer immunotherapy.

Currently, two TMRs are undergoing human clinical trials in Taiwan. CC-01 (Tucidinostat plus Celecoxib) is in a phase Ib clinical trial (ClinicalTrials.gov Identifier: NCT05281276) for the third-line treatment of advanced metastatic colorectal cancer. CT-01 (Tucidinostat combined with Regorafenib) is in a phase Ib/II clinical trial (ClinicalTrials.gov Identifier: NCT05770882) for the second-line treatment of intermediate or advanced HCC.

A new generation of epigenetic immunoactivator screening platform

Epigenetic modulators such as HDACis have been developed for at least 20 years, and several drugs have been approved as targeted drugs for marketing. But 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 activity 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 tumor microenvironment-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.

GNTbm has filed global patent application for GNTbm-38, and US patent has been granted. GNTbm-38 is currently undergoing preclinical studies and will be applied for INDs in the United States, Taiwan and China. GNTbm-38 is one of the backbone drugs of TMRs independently developed by GNTbm.

A new generation of epigenetic immunoactivator screening platform

Tyrosine Kinase Inhibitor (TKI) is a well-known anti-cancer drug that has 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 tumor microenvironment, when combined with a specific type of HDAC inhibitor, can activate and awaken the host immune system by remodeling the tumor microenvironment, which will lead to significant anti-cancer activity, long-term immune memory, and long-lasting remission without tumor recurrence, in so-called cancer immunotherapy.

TMRs in cancer immunotherapy refer to combination of drugs (except immune checkpoint inhibitors) with unique tumor microenvironment-regulating mechanisms to remodel the tumor microenvironment, 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 tumor microenvironment. The TMRs developed by GNTbm will be “GNTbm-38+X”, in which X can be a known TKI or a TKI independently developed by GNTbm according to the indications developed to achieve the best therapeutic benefits.

After years of research, the R&D team of GNTbm has independently developed a new chemical structure of multi-kinase inhibitor GNTbm-TKI with immunoregulating activity, one of the backbone drugs for TMRs. In vivo animal tests have also confirmed that by oral administration GNTbm-TKI in combination with GNTbm-38 obtains more than 80% of ORR in anti-cancer activity, and produces immune memory to inhibit tumor recurrence. The GNTbm R&D team is conducting more animal tests.

GNTbm-TKI will be filed for a global patent application.