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Indoximod-based chemo-immunotherapy for pediatric brain tumors: a first-in-children phase 1 trial

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 1 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 x5 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 non-responders (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 2/3 trials for pediatric brain tumors.

 

Comments:

This research study investigates the use of indoximod, an oral inhibitor targeting the metabolic checkpoint indoleamine 2,3-dioxygenase (IDO), in children with recurrent brain tumors or newly-diagnosed diffuse intrinsic pontine glioma (DIPG). The study involved two separate arms: one combining indoximod with oral temozolomide and another with palliative conformal radiation. Blood samples were collected and analyzed using advanced sequencing techniques.

Key Findings:
1. **Patient Population:** The study included 81 patients with recurrent brain tumors. The median overall survival (OS) for all patients with recurrent disease was 13.3 months. For DIPG patients, the median OS was 14.4 months.

2. **Combination Therapy:** Indoximod was combined with chemotherapy (temozolomide) and radiation. The maximum tolerated dose was not reached, indicating that the treatment was well-tolerated by the patients.

3. **Dose Determination:** The pediatric dose of indoximod was established at 19.2 mg/kg/dose, administered twice daily.

4. **Treatment Response:** Patients who exhibited an objective response (partial or mixed response) had a significantly longer median OS (25.2 months) compared to non-responders (7.3 months). Four patients remained disease-free for more than 36 months.

5. **Immune Response:** Single-cell sequencing revealed the emergence of new circulating CD8 T cell clonotypes with a late effector phenotype, indicating a positive immune response to the treatment.

**Conclusion:** Indoximod, in combination with chemotherapy and radiation, was well-tolerated and showed promising preliminary efficacy in children with recurrent brain tumors, including DIPG. These encouraging results support the progression of this treatment approach to Phase 2/3 trials for pediatric brain tumors.

Related Products

Cat.No. Product Name Information
S7756 Indoximod Indoximod, a methylated tryptophan, acts as an IDO (indoleamine-(2,3)-dioxygenase) pathway inhibitor, and reverses IDO-mediated immune suppression. Phase 2.This product has poor solubility, animal experiments are available, cell experiments please choose carefully!

Related Targets

IDO/TDO