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

Abstract 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...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2024-02, Vol.26 (2), p.348-361
Main Authors: Johnson, Theodore S, MacDonald, Tobey J, Pacholczyk, Rafal, Aguilera, Dolly, Al-Basheer, Ahmad, Bajaj, Manish, Bandopadhayay, Pratiti, Berrong, Zuzana, Bouffet, Eric, Castellino, Robert C, Dorris, Kathleen, Eaton, Bree R, Esiashvili, Natia, Fangusaro, Jason R, Foreman, Nicholas, Fridlyand, Diana, Giller, Cole, Heger, Ian M, Huang, Chenbin, Kadom, Nadja, Kennedy, Eugene P, Manoharan, Neevika, Martin, William, McDonough, Colleen, Parker, Rebecca S, Ramaswamy, Vijay, Ring, Eric, Rojiani, Amyn, Sadek, Ramses F, Satpathy, Sarthak, Schniederjan, Matthew, Smith, Amy, Smith, Christopher, Thomas, Beena E, Vaizer, Rachel, Yeo, Kee Kiat, Bhasin, Manoj K, Munn, David H
Format: Article
Language:English
Subjects:
Brain Neoplasms - drug therapy
Brain Neoplasms - pathology
Brain Stem Neoplasms - pathology
Child
Humans
Immunologic Factors
Immunotherapy
Temozolomide
Tryptophan
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Summary:Abstract 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.
ISSN:1522-8517
1523-5866
DOI:10.1093/neuonc/noad174