Uncovering the anti-cancer mechanisms of Immuno-Oncology

Uncovering the anti-cancer mechanisms of Immuno-Oncology

GNTbm has focused on immuno-oncology in recent years. By exploring the dynamic and complex tumor microenvironment, GNTbm has developed the optimal anti-cancer regimen with synergistic effect of combination of both immune checkpoint inhibitor and immune modulator with novel mechanism. Immunotherapy is a novel anti-cancer therapy, which will restart the body’s natural anti-tumor immune response for efficient killing of cancer cells for such a long time, so that there is a chance to make cancer curable or become a controllable chronic disease.

The development of the novel drug regimen for regulation of tumor microenvironment

To improve the anti-cancer immune response in the tumor microenvironment, which is the key factor controlling the immune response by immune checkpoint inhibitors (ICIs), our research team has focused to study how to facilitate the inhibition of tumor growth by regulating the immune components in the tumor. The immune checkpoint inhibitors have been the highlights for providing clinical benefit in complete regression and long-term survival in some patients, however not all patients respond. The average response rate was low in several approved new indications by monotherapy treatment with immune checkpoint inhibitors, such as anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies. The strategies of new drug combination with immune checkpoint inhibitors are the recent approaches of boosting the response rate of these ICIs. This will give opportunities for more patients with varieties of advanced cancers to assess the benefits of immunotherapy.

GNTbm provides a drug combination with high potential for controlling tumor microenvironment to boost immune response

In our research, the best treatment combination was demonstrated to efficiently improve the immune response rate and survival in animal studies. The best regimen includes chidamide plus generic drug C combined with ICI. Chidamide (tradename Kepida® in Taiwan and Epidaza® in China) is a novel and orally active benzamide class of histone deacetylase inhibitor (HDACi). It was also known as HBI-8000 in US and Japan. It is a subtype-selective HDACi inhibiting the enzyme activity of HDACs 1, 2, 3, and 10. Chidamide was approved by the China FDA for relapsed or refractory peripheral T-cell lymphoma in 2014 and granted as orphan drug designation in Japan in 2015. Moreover for cancer treatment, chidamide combined with endocrine therapy drug exemestane was shown to significantly improve the median of progression free survival (mPFS) in patients with ER+/Her-2- advanced breast cancer. The positive results of pivotal phase III study has been published in ESMO 2018 by originator company Chipscreen.

Chidamide is an HDAC-selective epigenetic modulator and generic drug C is a well-known commonly used non-oncologic generic drug. In our research, chidamide combined with ICI only partially improves immune response rate and survival compared to ICI alone. However the regimen of chidamide plus generic drug C (CC Combination) combined with ICI was demonstrated to show the disappearance of tumor in high percentage of treated tumor-bearing mice and also prolonged the survival significantly.


New drug combination to solve the drug resistance issue of ICIs

Chidamide plus generic drug C only possesses partial immune regulation activities, which further in combination with ICI was shown to produce powerful immune response activities in tumor-bearing mice with normal immune system, and influence the expression of genes such as cytokines, chemokines, and growth factors in the tumor microenvironment. The expression of genes especially related to interferon gamma, TNF alpha, and granzyme, was significantly increased in the tumor microenvironment after treatment with chidamide plus generic drug C combined with ICI. Furthermore, it was demonstrated that the immunosuppressive cells such as tumor-associated macrophage (TAM), myeloid-derived suppressor cells (MDSCs), regulatory T-cells (Tregs) were influenced in term of cell number and function.

ICIs have been shown to be a very promising drug treatment in several advanced cancer and several indications had been approved by US FDA, EMA, and PMDA. However drug resistance to ICIs has caused the benefit of treatment less than expected. Many promising combination approaches have been underway in pre-clinical studies and clinical trials. The efforts of these promising combination regimens bring a lot of hope for solving the problem of drug resistance by improving the immune response rate and the efficacy. Based on our in vivo results, GNTbm may provide a solution with great potential for elimination of ICI drug resistance by showing significant increase of ORR and survival with our CC drug combination plus ICI.