IDO is a key enzyme in the normal regulation of the host's adaptive immune response. Its role in regulating the immune response was initially demonstrated when pregnant mice were given IDO inhibitors, resulting in the rejection of the unborn fetus by the maternal immune system.
Hatem Soliman, MD
Center for Women’s Oncology
Moffitt Cancer Center
Hatem Soliman, MD, is a medical oncologist specializing in breast cancer at the Center for Women’s Oncology at Moffitt Cancer Center, Tampa, Florida. He is also a member of the Experimental Therapeutics Program at Moffitt and participates in research on novel drug discoveries. He has served as principal investigator on clinical studies of IDO (indoleamine-(2,3)-dioxygenase) pathway inhibitors.
Please briefly describe your research as it relates to the IDO pathway.
My role in IDO pathway research began with the development of the first-in-human phase I trials for the lead compound from a collaboration between NewLink Genetics and the National Cancer Institute, 1-methyl-D-tryptophan, also known as indoximod. I have been responsible for the design and conduct of the early-phase trials using this compound since 2007. I have also been involved in some of the correlative science built into the trials to better understand the biologic activity of indoximod in patients with advanced cancer. I am currently the principal investigator on a study combining indoximod with docetaxel in the treatment of metastatic breast cancer.
How does IDO function in normal cells?
IDO is a key enzyme in the normal regulation of the host’s adaptive immune response. Its role in regulating the immune response was initially demonstrated when pregnant mice were given IDO inhibitors, resulting in the rejection of the unborn fetus by the maternal immune system. This occurs because the maternal immune system recognizes the paternal antigens as foreign, so IDO expressed in the placenta acts as a protective shield for the fetus during pregnancy. Hence, normal functioning of IDO is important in preventing damage from excessive immune activation and also in the suppression of certain pathogens such as toxoplasmosis and listeria. IDO does this by breaking down the essential amino acid tryptophan. Low tryptophan levels cause T cells to become inactive, thereby dampening the immune response in the host.
How do IDO inhibitors function as immunotherapy in cancer?
Tumor cells have figured out a way to hijack the IDO pathway to their advantage by overexpressing IDO in response to stimuli such as interferon gamma. Often, the source of the interferon gamma comes from activated T cells that have infiltrated the tumor. So, then the tumor cells can turn on IDO, deplete tryptophan within the tumor microenvironment, and make it very hostile for effector cells to function effectively against the tumor cells. The goal of IDO inhibitors is to reverse these effects so that once immune cells get into the tumor they don’t encounter this hostile environment and activate more effectively. Also, preclinical data suggest that IDO inhibitors like indoximod can synergize with chemotherapy agents such as taxanes in an immune-dependent way to kill tumors more effectively. That is the basis for our ongoing trial combining indoximod with docetaxel.
In your opinion, what is the most interesting recent clinical finding relating to IDO inhibitors?
So far, it appears that indoximod is very favorable as a single agent and in combination with dendritic cell vaccines or docetaxel. This makes indoximod an ideal candidate to experiment with novel combinations using IDO inhibitors to augment the immune response from other checkpoint inhibitors such as CTLA-4 and PD-1/PD-L1 antibodies. There are preclinical data to support this idea, and some clinical experience to support this as well. One melanoma patient who previously received ipilimumab on a clinical trial was subsequently treated with indoximod. This patient developed de novo autoimmunity in the form of autoimmune hypophysitis and experienced prolonged disease stabilization. This gives us hope that the response rates to the checkpoint inhibitors can be enhanced by incorporation of IDO inhibitors into cancer immunotherapy protocols.
What are some of the most significant unanswered questions surrounding the use of IDO inhibitors as anticancer therapy?
IDO is overexpressed by a wide variety of tumors, so additional trials are required to determine which disease types benefit the most from IDO inhibition. Also, it appears that IDO inhibitors will work best when used in combination with other immunomodulatory agents. Determining which are the optimal combinations to use will require additional clinical trials as well.
Finally, there are different IDO pathway inhibitors in development. Some of the inhibitors directly inhibit the IDO enzyme, while others such as indoximod block the downstream effects of IDO activation. We are still determining if blockade of IDO activity at one point in the pathway or blocking both the enzyme and downstream effects is the optimal strategy going forward.