Novel dual arginase 1/2 inhibitor OATD-02 (OAT-1746) improves the efficacy of immune checkpoint inhibitors

Abstract

Background: The immunotherapeutic approach, adoptive cell transfer (ACT) have in malignant melanoma studies showed clinical durable responses in more than 50% of patients. However, the expansion of tumor infiltrating lymphocytes (TILs) requires extensive ex vivo culturing often at the cost of T cell differentiation and functional capacity. Most current strategies involve non-specific expansion of bulk TILs, often providing growth preference to co-infiltrated virus specific T cells and driving an exhausted phenotype of the T cell product. Methods: It is aimed to develop a new technology to expand tumor reactive T cells, through use of Major histocompatibility complex (MHC)-loaded artificial antigen-presenting scaffolds (Ag-scaffold) to provide the T cells with specific functional stimulation to obtain phenotypic and functional properties to mediate tumor regression. These scaffolds will be build using a dextran-based polysaccharide backbone associated with streptavidin molecules where biotinylated peptide-MHC class I molecules are attached to govern the specific interaction with a specific T cell, and a combination of biotinylated cytokines and co-stimulatory molecules are co-attached to provide stimulation to the T cell to achieve increased functional properties. The Ag-scaffolds interacts specifically with T cells based on recognition of the peptide-MHC molecule and effectively expand and functionally stimulate specific T cells, while leaving all other T cell specificities untouched. Results: from in vitro experiments have showed that antigen specific CD8 T cells stimulated with these Ag-scaffolds has high CD28 expression and low PD-1 expression, associated with high proliferation potential and enhanced antitumor effect in vivo. Furthermore, this expansion strategy provides a high frequency of multifunctional antigen specific CD8 T cells expressing IFN-, TNF-a, and CD107a upon target recognition. Conclusions: This expansion technology could with great advantage be used in ACT, to increase the anti-tumor effect of the transferred T cell product, as all of the achieved T cell characteristics are of significant importance for in vivo tumor cell recognition following ACT of expanded T cell products.