Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Neuro-oncology (Charlottesville, Va.), 2024-02, Vol.26 (2), p.348-361

Ort / Verlag

England

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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. 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. 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. 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.