Not only is IDO expressed on tumor cells, but it also is present on cells in the surrounding microenvironment, such as dendritic cells (DCs) in the tumor-draining lymph nodes (Figure). DCs are responsible for activating the T cells by presenting them with foreign antigens. However, DCs that overexpress IDO actually inhibit the activation of effector T cells and drive their conversion into regulatory T cells, thereby further suppressing the immune response. By driving IDO overexpression, tumors are able to create an immunosuppressive microenvironment in which to reside.Potential for Synergy
Given its role in sheltering tumors from the immune system, IDO makes an ideal target for anticancer immunotherapy. Cancer immunotherapy typically involves the stimulation of a patient’s immune system so that it recognizes tumor cells as foreign and attacks them—usually through immunization with a vaccine or administration of a therapeutic antibody.
administration of a therapeutic antibody. However, researchers are beginning to appreciate that not only do we need to present the immune system with antigens to attack, but we also need to overcome tumor-induced tolerance of these antigens that antagonizes the function of immunotherapy and limits its efficacy. This is where IDO-targeted agents could potentially truly come into their own. Because IDO expression helps to create this state of tolerance, IDO inhibition could enhance the efficacy of other immunotherapies as well as chemotherapy and radiation therapy.Development of IDO Inhibitors
There are a number of chemicals and other small molecules that have been found to act as IDO inhibitors. These include those based on natural products, such as the cabbage extract brassinin, the marine hydroid extract annulin B, and the marine sponge extract exiguamine A. Synthetic derivatives for each of these substances are being prepared and evaluated in preclinical testing.
IDO can also be inhibited by molecular analogs of its substrate, tryptophan, and this is where the most significant clinical development has occurred. 1-methyl tryptophan (1-MT) is a tryptophan mimetic found as two stereoisomers: dextrorotary (D) and levorotary (L). The L isomer significantly inhibits IDO1, while the D isomer more significantly inhibits IDO2. The D isomer was selected for clinical translation by NewLink Genetics Corporation and the National Cancer Institute as indoximod.
Indoximod was well tolerated (the most frequent adverse events were fatigue and anemia) and showed promising signs of anticancer activity. Four of 22 patients experienced partial responses and 9 of 22 experienced stable disease in a phase I dose-escalation study in patients with advanced solid tumors (NCT01191216). To evaluate the potential of indoximod to enhance the efficacy of other therapies, it was also evaluated in a phase I trial in combination with a DC vaccine directed against p53. Results presented at the 2013 American Society of Clinical Oncology Annual Meeting in Chicago suggested that the immunotherapy sensitized patients to subsequent therapies. Seven of 19 patients treated with subsequent chemotherapy had an objective response, including 6 of 11 patients who received gemcitabine-based therapy (NCT01042535). Indoximod is currently being evaluated in a phase II, double-blind, randomized, placebo-controlled trial in patients with breast cancer (NCT01792050). NewLink Genetics also has an active program directed at synthesizing other IDO pathway inhibitors.
A second IDO inhibitor is in clinical trials. INCB024360 is an orally available hydroxyamidine small-molecule inhibitor. Unlike 1-MT-based inhibitors, hydroxyamidine inhibitors also inhibit tryptophan (2,3)-dioxygenase (TDO), an enzyme with identical activity to IDO. A recent study implicated TDO in the development of cancer in a similar manner to IDO, and many in the field believe it will be important to inhibit both IDO and TDO to overcome any compensatory mechanism. INCB024360 is in phase II trials in patients with unresectable or metastatic melanoma (NCT01604889) and ovarian cancer (NCT01685255).
Several other companies also are directing preclinical research programs at IDO inhibitor development. iTeos Therapeutics, a spinoff of the Ludwig Institute for Cancer Research and the de Duve Institute at the Université catholique de Louvain in Belgium, was launched two years ago specifically to develop novel immunotherapies for cancer treatment. It has both IDO and TDO inhibitors in preclinical development. ToleroTech Inc and Bio-Matrix Scientific Group Inc are developing small interfering (si)RNA-based cancer vaccines designed to treat cancer by silencing immunosuppressive molecules such as IDO. While Tolerotech is evaluating the value of these agents in melanoma, Bio-Matrix is focusing on breast cancer.
Because it contains heme iron in its active site that is easily inactivated by oxidation, IDO is only active in a low-oxygen (hypoxic) environment. A number of hybrid hypoxia-targeting IDO inhibitors (eg, TX-2274) have been designed to take advantage of this fact and are in preclinical development. Meanwhile, the search for other, more effective IDO-targeting agents continues, aided by the recent elucidation of the crystal structure of the IDO protein. The future looks bright for the inhibition of checkpoint proteins as a therapeutic strategy in oncology.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in Davis, California.
Ino K, Tanizaki Y, Kobayashi A, et al. Role of the immune tolerance-inducing molecule indoleamine 2,3-dioxygenase in gynecologic cancers. J Cancer Sci Ther. 2012; S13.
Jackson E, Dees EC, Kauh JS, et al. A phase I study of indoximod in combination with docetaxel in metastatic solid tumors. J Clin Oncol. 2013;31(suppl; abstr 3026).
Löb S, Königsrainer A, Rammensee HG, et al. Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat Rev Cancer. 2009;9(6):445-452.
Nakashima H, Ikkyu K, Nakashima K, et al. Design of novel hypoxia-targeting IDO hybrid inhibitors conjugated with an unsubstituted L-TRP as an IDO affinity moiety. Adv Exp Med Biol. 2010;662:415-421.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4): 252-264.
Smith C, Chang MY, Parker KH, et al. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov. 2012;2(8):772-735.
Soliman HH, Minton SE, Han HS, et al. A phase I study of ad.p53 DC vaccine in combination with indoximod in metastatic solid tumors. Presented at: 2013 ASCO Annual Meeting; May 31-June 4, 2013; Chicago, IL. Abstract 3069.
Wainwright DA, Dey M, Chang A, et al. Targeting Tregs in malignant brain cancer: overcoming IDO. Frontiers Immunol. 2013;4(116):1-17.