AUGUSTA, Ga.—The National Cancer Institute is sponsoring the first study examining the efficacy of indoximod, a drug that inhibits an enzyme that certain pediatric tumors use to shield themselves from a child’s natural immune response. The study, led by pediatric oncologists at the Medical College of Georgia and Georgia Cancer Center, is enrolling children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine gliomas, aggressive tumors for which there is no current curative therapy.
The Phase 2 trial will explore whether adding indoximod—an inhibitor of the enzyme indoleamine 2,3 dioxygenase, or IDO—to children’s treatment will enable lower doses of chemotherapy and radiation, improve quality of life during treatment, and achieve improved survival for these children.
Drs. Theodore S. Johnson and David H. Munn, pediatric oncologists at the Georgia Cancer Center and Medical College of Georgia at Augusta University, are the lead investigators for the trial. The National Cancer Institute is funding the study with a $3-million grant. The study will take place at Augusta University’s Children’s Hospital of Georgia and Georgia Cancer Center, as well as at Emory University’s Children’s Heathcare of Atlanta.
The drug indoximod inhibits the enzyme IDO, which governs several important functions of the immune system, including avoiding food allergies and tolerating microorganisms in the gut which are helpful but foreign to the body. IDO suppresses T cells and promotes activation of regulatory T cells that suppress it. IDO is involved in the immune response to a variety of scenarios including tumors, blood cancers, infections and organ transplants; high IDO expression has been documented in a variety of tumors and is associated with poor outcomes.
“In adults, the so-called ‘checkpoint-blockade’ immunotherapy has focused heavily on the PD-1 and CTLA-4 pathways; these molecules are expressed on T cells, and blocking them appears to work best when the tumors have many mutational neoantigens, and there are many activated T cells already present in the tumor, even before starting immunotherapy,” explains Munn. “In children, most pediatric tumors have fewer mutations, and are usually ‘cold’ and un-inflamed at baseline. Thus, our focus has been to look further upstream in the immune-activation process, specifically targeting the antigen-presenting cells (dendritic cells) that are needed to activate the T cells in the first place. This is where we hypothesize that IDO exerts its key effects.”
In preclinical studies and a recently completed Phase 1 trial for indoximod, the researchers found evidence that adding an IDO inhibitor to the current standard of care may help to enable a child’s natural immune response to attack a tumor more aggressively. Adding the IDO inhibitor indoximod to the treatment mix seems to help standard treatments work better at lower doses by setting the immune system free to respond as it should.
“In preclinical models, one of the important roles of IDO is to help enforce the immunosuppressive (tolerance-inducing) response to apoptotic cells,” says Munn. “Therefore, our hypothesis was that IDO might contribute to suppression of the anti-tumor immune response to dying tumor cells during chemotherapy.” He adds that the same may be true for the body’s response to radiation therapy, which also kills tumor cells.
“It isn’t that the immune system is asleep at the switch and doesn’t know it’s supposed to be attacking,” he notes. “It’s actively suppressed. The idea … is to remove the brakes from a system that would like to attack the tumor.”
“We also have evidence that the addition of an IDO inhibitor to these children’s treatment will help us reduce the toxicity often associated with aggressive cancer treatment, improve quality of life during treatment, and in some cases offer at least the potential for cure,” Johnson commented in a media release announcing the Phase 2 trial.
The trial comes on the heels of a successful first-in-children Phase 1 trial of indoximod, led by Johnson and Munn, which enrolled more than 80 pediatric patients. The researchers plan to publish a paper detailing their results within the year.
According to Munn, “We found that patients tolerated the combined treatment very well. This meant that they were able to receive prolonged treatment (sometimes for years) in an outpatient setting. This low toxicity in combination with conventional chemotherapy and radiation is especially important for our pediatric population, where optimizing quality of life and treatment-related toxicities are important considerations.”
“Indoximod has been remarkably well tolerated in our pediatric patients, and so far we have not seen limiting autoimmune or inflammatory toxicities,” he continues. “The immune system appears able to compensate for even prolonged treatment with an IDO-inhibitor drug. Our speculation is that the tumor is much more critically dependent on the IDO mechanism when it is forced to maintain tolerance to itself under the wave of dying tumor cells and antigen-release following chemotherapy. Thus, our hypothesis is that the normal immune system is able to compensate for the inhibition of IDO, but the chemotherapy-damaged tumor is not. This is why the combination of an IDO-inhibitor with chemotherapy (or, by analogy, with radiation) is so attractive.”
The upcoming study will involve treating 91 pediatric patients with recurrent ependymomas, meduloblastomas and glioblastomas with indoximod in combination with chemotherapy, and with or without low-dose radiation therapy. The trial also will provide frontline treatment to 30 pediatric patients with newly diagnosed diffuse intrinsic pontine glioma; for these patients, the trial pairs indoximod and radiation followed by maintenance therapy with chemotherapy and indoximod.
Brain tumors are the most common tumors in children. Diffuse intrinsic pontine gliomas are aggressive and difficult-to-treat tumors that are typically found at the base of the brain, in an area that controls basic body functions like breathing and heart rate. Their location rules out surgery, and current treatment includes radiation therapy and typically produces only a short-term response.
“The literature would suggest that the IDO pathway is widely expressed in many types of tumors,” says Munn. “Perhaps even more importantly, when we combine an IDO-inhibitor with chemotherapy, our target is the IDO that is expressed by the host antigen-presenting cells (such as dendritic cells), not by tumor cells. Thus, we hypothesize that we are targeting a basic inhibitory pathway in the immune system, not a peculiarity of one particular tumor type. As such, we anticipate that IDO-based chemo-immunotherapy it is likely to operate across many types of tumor, and with a variety of chemotherapy drugs.”
