07-09 April 2019

Dr. Gianluca Fossati, Head of Biochemistry and Molecular Biology at Italfarmaco will present at the forthcoming Gordon Research Conference on Cancer Genetics and Epigenetics to be held on April 07-12, 2019 at Renaissance Tuscany Il Ciocco in Lucca (Barga), Italy.

Italfarmaco is a leading Company in the design and development of new generation selective HDAC inhibitors. We have designed potent, orally active, small molecule HDAC6 inhibitors with high selectivity and an unprecedented tolerability profile.

Anticancer immunotherapy with antibodies directed to the so-called immune checkpoint molecules gives impressive results with long-lasting tumor regression obtained, however, only in a fraction of patients. To overcome the so far suboptimal results, different targets and combination therapies are the aim of a number of ongoing clinical and non-clinical studies. HDAC6 is a member of the Zn-dependent histone deacetylase family of enzymes and is a promising target for the modulation of the immune response, particularly within the tumor microenvironment.

We have studied the effect of a selective HDAC6 inhibitor, ITF3756, in in vitro and in in vivo non-clinical models. In particular, we found that in vivo, ITF3756 was as effective as an antibody against PD-1 (an immune checkpoint molecule) and that the combination of the two treatments additionally improved the reduction of tumor growth. T cells from the spleen of animals treated with ITF3756 showed a specific response when stimulated ex vivo with tumor derived immunogenic peptides, suggesting that the antitumor activity of the molecule was mediated by the immune system. In agreement with this hypothesis, the compound was completely ineffective in immunodeficient SCID/beige mice bearing the same tumor.

This study shows in vitro and in vivo mechanisms whereby ITF3756 increases the immune response and constitute a robust basis for a rationale use of a selective HDAC6 inhibitor either alone or in combination for the induction of antitumor immune response.