Novel small molecule HDAC-inhibitor: potential game changer to fight immune evasive cancers

A novel Inhibitor binding to a specific HDAC molecule reduces the ability of tumors to hide from the immune system and increases the ability of immune cells to attack tumors. This might widen the use of promising Antibody based tumor therapies also to those cancer types, where tumors evade from the immune system.

Challenge

Some of the most dangerous cancer types like pancreatic cancer (PDAC) or Glioblastoma, exploit this regulatory mechanism by creating a tumor micro-environment (TME) that provides resistance to immune system attack and promotes tumor growth. This prevents the use of promising antibody-based therapies. Currently strategies to overcome the immune evasion like Immune-Checkpoint-Inhibitors (ICIs) or mRNA-vaccination are insufficient, since they can cause significant side effects like autoimmune responses or do not address the core of the problem, the immune evasion.
DNA methylation and histone-acetylation / -deacetylation play a central role in the regulation of gene expression and carcinogenesis. Epigenetic changes e.g. in the expression of HDACs can disrupt processes such as cell cycle regulation and immune surveillance.

Our Solution

We found a novel HDAC inhibitor, that has an influence on immune reactions in the TME in several cancer types. In contrast, to well known inhibitors to this HDAC, the Molecule FM43 resulted in an increase of MHC-class1 expression in different pancreas tumor cell-lines and could increase the activity of CAR-T cells (Figure1).

Figure 1: Three different Pancreas Tumor cell-lines (MiaPaCa-2, PSN1 and AsPC1 – data not shown for the latter two) were treated with the HDAC inhibitor FM43 and analyzed for MHC-I presentation by flow cytometry. Signal: Fluorescence detected from stained MHC-I.

Figure 2: FM43 enhances T cell mediated co-killing: Primary DLBCL-Blood cells (B-cell-Lymphoma cells) were co-cultured with CD19 CAR-T cells and 5µM of FM43 for 24h.

Our lead candidate FM43 also succeeded to enhance the killing of B-Cell Lymphoma cells with CAR-T cells, while showing no toxicity in cell culture. Thus it is anticipated, that the novel HDAC inhibitor has a different mechanism of action as compared to the known HDAC inhibitors. This novel type of action opens up a first in class opportunity.

Advantages

he novel small molecule FM43 enhances MHC-I presentation in B-cell lymphoma and Pancreatic cancer
Synergy with AB-based Cancer therapies and CAR-T cell based therapies possible
A potentially new mechanism of action provides first in class aspects
Mechanism of action and in vitro data indicate low side effects
Enhanced killing of Tumor cells is proven
patent application covers a novel class of small molecule drugs
Potential indications are all cancer types, that evade from immune System like Liver-, Pancreatic-, Prostate-, Colorectal- and Non-Small Cell Lung Cancer (NSCLC), Renal Cell Carcinoma, Hodgkin’s Lymphoma, Hepatocellular Carcinoma, Glioblastoma, Germ Cell Cancersthyroid cancers

Applications

Development Status

Preclinical: Proof of concept vs different Cancer cell lines

Patent Status

A Priority patent application has been filed in the name of the University Medical Center of Göttingen and the Martin-Luther-Universität Halle-Wittenberg – Worldwide IP-Rights possible.