A Phase I study of NLG919 for adult patients with recurrent advanced solid tumors

Background The enzyme Indoleamine 2,3-dioxygenase (IDO1) catalyzes the cleavage of L-tryptophan, resulting in the production of kynurenine. Tryptophan depletion and kynurenine metabolites enhance the number and function of Tregs (suppressive arm) and inhibit effector T cells (stimulatory arm), regulating acquired local and peripheral immune tolerance. In cancer, IDO can either be expressed directly by the tumor cells themselves, or induced indirectly in host antigen presenting cells by the tumor and its expression has been associated with a worse clinical outcome in a variety of cancers. Indoximod (1-methyl D-tryptophan), the first IDO pathway inhibitor to enter human clinical trials, is currently being tested in multiple Phase II clinical trials. We are here to report preliminary Phase I data with another promising IDO pathway inhibitor, NLG919, a potent direct enzymatic inhibitor of IDO. While Indoximod and NLG919 both target the same IDO pathway, preclinical data clearly demonstrates that these compounds have different mechanisms of action and are synergistic. In preclinical models, NLG919 showed dosedependent activation and proliferation of effector T cells, producing dramatic regression of large established tumors. Additionally, NLG919 showed enhanced immune activation and tumor regression when combined with Indoximod in this system.