Adil Daud, MD
As researchers continue to explore immune checkpoints as targets for anticancer therapies, the IDO pathway has emerged as the leading contender to yield the next batch of new drugs in the field. Clinical trial results thus far have been particularly promising for IDO inhibitors combined with antibodies that target the PD-1/ PD-L1 pathway.
The IDO protein, or indoleamine (2,3)-dioxygenase, has been identified as a checkpoint protein involved in generating the immunosuppressive tumor microenvironment that supports tumor growth. The enzyme has 2 isoforms, IDO1 and IDO2, that act as the first step in the metabolic pathway that breaks down the essential amino acid tryptophan.
IDO exerts its immunomodulatory effects by shutting down the effector T cells of the immune system. Increased IDO protein levels then drive growth arrest and apoptosis of the effector T cells, a group of immune cells that includes cytotoxic T cells, helper T cells, and natural killer cells that mediate the immune system’s ability to destroy pathogens. By reducing the number of effector T cells, IDO overexpression prevents the immune system from effectively destroying cancer cells.
Researchers have discovered that IDO is expressed on tumor cells and on cells in the surrounding microenvironment, such as dendritic cells in the tumor-draining lymph nodes (Figure
). This offers multiple opportunities for targeting the tumorigenic activities of aberrant IDO signaling.
IDO overexpression has been observed in numerous solid tumors, prompting pharmaceutical developers to evaluate pathway inhibitors in a variety of clinical settings. At least 5 IDO inhibitors are in development (Table
), mostly in combination with other immunotherapies including therapeutic vaccines and checkpoint blockade agents, or with standard chemotherapies.
Excitement about the potential for the drugs as a class is building. “Everything is starting to come together for these IDO inhibitors,” said Adil Daud, MD, a leading IDO researcher who is a clinical professor at UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, in an interview with OncologyLive®
. “For the last few years, there has been a lot of basic science research done showing that IDO is a fundamental mechanism that keeps pregnancy going, is involved in the immune system, and senses the tumor microenvironment.
“Now, this current generation of inhibitors is in testing, and they seem to be relatively nontoxic when they’re added to PD-1,” he said. “I think that’s something exciting considering all the immune checkpoint combinations that people are talking about. It seems like they can be combined and have a reasonable rate of activity, with the caveat that, currently, we are just talking about phase II trials.”
The most advanced agent under study is epacadostat, an orally available inhibitor of IDO1. Findings from early-phase studies into epacadostat have been promising, particularly in melanoma, where the drug is being paired with the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) in separate studies.
In phase I study results, 11 of 19 evaluable treatment-naïve patients with melanoma who received the combination achieved an objective response (58%), including 5 patients (26%) with a complete response (CR) and 6 (32%) with a partial response (PR).1
The disease control rate, which consisted of CRs, PRs, and stable disease, was 74% (14 patients).
The combination has advanced into a pivotal phase III study. The KEYNOTE-252/ECHO-301 trial will randomize 600 patients in a 1:1 ratio to pembrolizumab with either epacadostat or placebo (NCT02752074). The trial is recruiting patients with stage III/IV melanoma who have not received prior or systemic therapy for metastatic or unresectable disease.
Similarly, the pairing of epacadostat and nivolumab has shown positive early results in patients with melanoma. The combination demonstrated an objective response rate (ORR) of 63% and a CR rate of 5% among 74 patients with treatment- naïve melanoma in the multiarm phase I/II ECHO-204 trial, according to findings presented at the 2017 American Society of Clinical Oncology Annual Meeting in June.2