Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial

Neuro Oncol. 2024 Feb 2;26(2):348-361. doi: 10.1093/neuonc/noad174.


Background: 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.

Keywords: IDO; brain cancer; immunotherapy; indoximod; pediatric.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / pathology
  • Brain Stem Neoplasms* / pathology
  • Child
  • Humans
  • Immunologic Factors
  • Immunotherapy
  • Temozolomide
  • Tryptophan


  • 1-methyltryptophan
  • Temozolomide
  • Tryptophan
  • Immunologic Factors

Associated data