IDO1 Inhibitors in Combination with Immunotherapy for the Treatment of Glioblastoma

Abstract

The immune system in patients with cancer is often markedly impaired, with tumours utilising a variety of methods to subvert anti-tumour immune responses. One mechanism whereby tumours can induce immune suppression involves increased expression of the enzyme indoleamine 2, 3-dioxygenase 1 (IDO1). This enzyme catalyses the degradation of the essential amino acid tryptophan along the kynurenine pathway. IDO1 is expressed in a broad range of cancers and is correlated with increased immune suppression and poor patient survival. IDO1 inhibitors would therefore be expected to be beneficial for restoring antitumour immunity in cancer patients. High throughput screening of compound libraries has led to the discovery of a novel chemical class of IDO1 inhibitors, from which SN35837 has been selected for development into a potential anti-cancer agent. Preliminary studies of SN35837 in a preclinical model of glioma have yielded encouraging results. Kynurenine:tryptophan (K:T) ratios are commonly used as an indicator of IDO1 activity, and a sensitive HPLC assay detecting both tryptophan and kynurenine concentrations in biological samples was established to measure K:T ratios in tissues collected from tumour bearing mice. Daily administration of SN35837 was shown to suppress K:T ratios in both tumour and plasma of tumour bearing mice, reflecting the ability of SN35837 to inhibit IDO1 activity. The level of K:T ratio suppression was dose dependent and lasted between 2 to 6 hours after treatment, depending on the dose. Preclinical studies have recently shown that combinatorial targeting of immunosuppression is a strategy that has high potential value for the treatment of cancer, including malignant glioma. With SN35837 identified as a potent inhibitor of IDO1, experiments were conducted to obtain proof-of-principle that combining IDO1 inhibition with other immunotherapeutic approaches could lead to improvements over monotherapy. To this end, SN35837 was tested in combination with PD-1 immune checkpoint blockade resulting in improved survival of tumour bearing mice. Combination of SN35837 with a whole cell glioma vaccine, however, did not provide improvements over control. The work in this thesis highlights the in vivo efficacy of SN35837 as an inhibitor of IDO1 and point to its combination with immune checkpoint blockade as a potential treatment for cancer.