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Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trialShow simple item record

dc.creatorJohnson, Theodore S.
dc.creatorMacDonald, Tobey J.
dc.creatorPacholczyk, Rafal
dc.creatorAguilera, Dolly
dc.creatorAl-Basheer, Ahmad
dc.creatorBajaj, Manish
dc.creatorBandopadhayay, Pratiti
dc.creatorBerrong, Zuzana
dc.creatorBouffet, Eric
dc.creatorCastellino, Robert C.
dc.creatorDorris, Kathleen
dc.creatorEaton, Bree R.
dc.creatorEsiashvili, Natia
dc.creatorFangusaro, Jason R.
dc.creatorForeman, Nicholas
dc.creatorFridlyand, Diana
dc.creatorGiller, Cole
dc.creatorHeger, Ian M.
dc.creatorHuang, Chenbin
dc.creatorKadom, Nadja
dc.creatorKennedy, Eugene P.
dc.creatorManoharan, Neevika
dc.creatorMartin, William
dc.creatorMcDonough, Colleen
dc.creatorParker, Rebecca S.
dc.creatorRamaswamy, Vijay
dc.creatorRing, Eric
dc.creatorRojiani, Amyn
dc.creatorSadek, Ramses F.
dc.creatorSatpathy, Sarthak
dc.creatorSchniederjan, Matthew
dc.creatorSmith, Amy
dc.creatorSmith, Christopher
dc.creatorThomas, Beena E.
dc.creatorVaizer, Rachel
dc.creatorYeo, Kee Kiat
dc.creatorBhasin, Manoj K.
dc.creatorMunn, David H.
dc.date.accessioned2024-09-25T21:35:57Z
dc.date.available2024-09-25T21:35:57Z
dc.date.issued9/16/2023
dc.identifier.urihttps://doi.org/10.1093/neuonc/noad174
dc.identifier.urihttps://repository.tcu.edu/handle/116099117/65963
dc.descriptionBackground. Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy.Methods. We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing.Results. Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype.Conclusions. Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.
dc.languageen
dc.publisherOxford University Press (OUP)
dc.sourceNEURO-ONCOLOGY
dc.titleIndoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial
dc.typeArticle
dc.rights.licenseCC BY-NC 4.0
local.collegeBurnett School of Medicine
local.departmentBurnett School of Medicine
local.personsHeger (SOM)


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