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 antigenpresenting 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.Legal entity responsible for the study: Sine Reker Hadrup Funding: Lundbeck foundation Disclosure: All authors have declared no conflicts of interest.

Melanoma-associated fibroblasts impair CD8+ T cell function and modify expression of immune checkpoint regulators via increased arginase activity

“…This is interesting because arginase inhibitors, either alone or in combination with checkpoint inhibitors, are currently being tested as anti-neoplastic agents in various solid malignancies (NCT02903914). These clinical trials are in concert with preclinical data suggesting that arginase blockade may increase efficiency of the PD-1/PD-L1 blockade [52,53]. Thus, our data may support the notion that arginase inhibition may be a tool that makes some solid tumors more vulnerable to multiple forms of ICR-blockade.…”

Influence of Tumor Microenvironment and Fibroblast Population Plasticity on Melanoma Growth, Therapy Resistance and Immunoescape

“…Furthermore, the selective arginase inhibition blocks MAF-induced TIGIT and BTLA expression on cytotoxic T cells [187]. This experimental evidence is in line with other studies showing that arginase inhibition can increase the efficiency of the PD-1/PD-L1 blockade [190,191]. Therefore, all these studies suggest that MAFs, as melanoma cells, may contribute to the generation of a tolerogenic and immunosuppressive melanoma microenvironment by altering the availability of immune-modulating metabolites, such as glucose, arginine and lactate, in the extracellular environment (Figure 3).…”

Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective

“…The same biopharmaceutical company developed a novel orally dosed arginase inhibitor CB-280 (undisclosed structure), which already entered phase I trials for the treatment of cystic fibrosis [ 181 ]. Another novel Arg1 and Arg2 inhibitor, OATD-02 by OncoArendi Therapeutics SA (undisclosed structure, IC 50 < 50 nM [ 182 ]), is also expected to enter phase I trials mid-2020 to evaluate its ability to inhibit the proliferation and immune escape of cancer cells [ 172 ]. The combination of third-generation arginase inhibitors with other immune checkpoint inhibitors in a mouse glioma model recently suggested improving therapeutic response [ 183 ], which opens new doors for the development and use of arginase inhibitors.…”