Phase I Trial of Indoximod in Combination with Temozolomide-based Therapy for Children with Progressive Primary Brain Tumors
Project Update (July 2019)
Dr. Johnson's ALSF grant has resulted in a multisite clinical trial called "Study of the IDO Pathway Inhibitor, Indoximod, and Temozolomide for Pediatric Patients With Progressive Primary Malignant Brain Tumors." The trial is available at Augusta University (Augusta, Georgia), Children's Healthcare of Atlanta (Atlanta, Georgia), Arnold Palmer Hospital for Children (Orlando, Florida) and the Children's Hospital Colorado (Aurora, Colorado)
This is a first-in-children phase 1 trial using indoximod, an inhibitor of the immune "checkpoint" pathway indoleamine 2,3-dioxygenase (IDO), in combination with temozolomide-based therapy to treat pediatric brain tumors. For more information, visit the ClinicalTrial.gov page.
Project Update (January 2016)
Ted Johnson answered questions about the progress of his research.
What do you study and what have you found?
The Johnson Lab studies mechanisms, such as the IDO pathway (indoleamine 2,3-dioxygenase), by which cancer can protect itself from rejection by the immune system. Cancers develop as the result of multiple genetic mutation which lead to alterations in the proteins coded by the cancer cells. The immune system is engineered to attack cells that have strange appearing “foreign” proteins because they may indicate infection. This is why a mismatched kidney is rapidly rejected after transplanting it into a different person. Tumors have plenty of target proteins to be rejected by the immune system, but they are usually not rejected because of mechanisms like the IDO pathway that suppress such immune responses. If we can learn enough about how the immune system is controlled by pathways like IDO, then we can target those mechanisms with new drugs like indoximod which blocks the IDO pathway.
We have used an animal model of glioblastoma to show that blocking IDO with indoximod during standard chemotherapy and radiation leads to high-grade inflammation in the tumor, kills tumor cells, and improves survival (1). This preclinical data has been used in support of phase 1 studies using indoximod in combination with temozolomide to treat both adults (NLG2102 / NCT02052648) and children (NLG2105 / NCT02502708) with relapsed brain tumors.
- Li M, Bolduc AR, Hoda MN, Gamble DN, Dolisca S, Bolduc AK, Hoang K, Ashley C, McCall D, Rojiani AM, Maria BL, Rixe O, MacDonald TJ, Heeger PS, Mellor AL, Munn DH, Johnson TS. The indoleamine 2,3-dioxygenase pathway controls complement activation in brain tumors following chemo-radiation therapy. Journal for Immunotherapy of Cancer: 2014; 2:21. doi:10.1186/2051-1426-2-21.
What is the status of the phase I trial?
The Pediatric Phase 1 trial NLG-2105 (NCT02502708), “Phase 1 trial of indoximod in combination with temozolomide-based therapy for children with progressive primary brain tumors,” is open and enrolling patients here at the Children’s Hospital of Georgia, Augusta University.
We are screening patients from around the country and elsewhere. Our 2nd site in Atlanta (Children’s Healthcare of Atlanta) is due to open in early 2016.
What did your ALSF-funded research grant make possible?
ALSF has funded both the preclinical scientific studies (‘A’ Award) and the Pediatric Phase 1 trial (Bio-therapeutics Impact Grant). The preclinical studies supported by the ‘A’ Award provided critical rationale for proceeding to clinical trials using indoximod IDO-blockade for patients with brain tumors. Prior to generating that data set, no IDO-blocking drugs were being developed for use against brain tumors of any kind. The Bio-Therapeutics Impact Grant from ALSF provided crucial support in opening the pediatric phase 1 clinical trial and in securing a commitment from the industry sponsor to run the trial.
What has surprised you about your research?
We were not expecting to move this fast from the laboratory to developing a new class of IDO-blocking drugs for clinical use in children. This was our goal, but we thought it would take much longer. We have been well supported by multiple foundations, in particular ALSF, and by the industry sponsor NewLink Genetics. Indoximod is not yet approved for any adult indication, so this is an area where we could only advance with the aid of large foundations like ALSF and the commitment of the drug manufacturer.
Where do you go from here – what are your next steps?
We have active collaborations with groups around the country to study IDO expression in archival biopsy samples from patients with various types of cancer. We are particularly interested in whether IDO protein is up-regulated when cancer relapses, which would make IDO an attractive target in that setting. We are developing additional IDO-based immunotherapy trials for children with brain tumors, and also for children with other types of cancer.
Immunotherapy treats cancer by enlisting the body's own immune system to specifically seek out cancer cells and eliminate them, ideally leaving normal tissue undamaged. Immunotherapy is safer, more natural, and far less toxic than "high-dose" chemotherapy -- and it is likely to work better in children because their underlying immune systems are stronger than adult immune systems. IDO is one of the best targets for immunotherapy. Normally, IDO is a natural mechanism the body uses to slow the immune system down, but IDO is often stolen by tumors to shield themselves against attacks by the immune system. Inhibiting IDO is one way to deny tumors this protection, and allow the immune system to activate and help kill the tumor.
We propose a first-in-children clinical trial using the drug indoximod to inhibit IDO, in combination with the chemotherapy drug temozolomide to treat children with brain tumors. Using an animal brain tumor model, we recently showed that adding IDO-blocking drugs to chemotherapy plus radiation enhances survival by triggering the immune system to attack the tumor. To guide our treatment of children, we have already opened a first-in-adult brain tumor clinical trial using indoximod plus chemotherapy (NCT02052648). This kind of cutting-edge combination immunotherapy/chemotherapy trial is now state-of-the-art in adults, but has not yet been made available to children. The goal of the proposed pediatric clinical trial is to bring IDO-based combination therapy into the clinic for children with brain tumors, who currently have few options and limited access to immunotherapy.
"Children with progressive brain tumors have a dismal prognosis with very few treatment options. Our goal is to change that, using immunotherapy that blocks the IDO 'immune-checkpoint' pathway and triggers anti-tumor immunity. The Bio-therapeutics Impact Grant from Alex’s Lemonade Stand Foundation is driving this science into the clinic by funding a first-in-children phase I trial to test the IDO-blocking drug indoximod in combination with conventional chemotherapy for children with relapsed or refractory pediatric brain tumors. This kind of high-impact chemo-immunotherapy trial has never been undertaken in pediatric patients, and the generous support of Alex’s Lemonade Stand Foundation is bringing the hope of these unique treatments to children and families who are out of standard treatment options." -Ted Johnson 1/2015