A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with indoximod in metastatic solid tumors and invasive breast cancer.

Hatem Soliman,Roohi Ismail-Khan,Hyo S Han,Marilyn M Bui,Fatema Khambati,Scott Antonia,Daniel M Sullivan

doi:10.18632/oncotarget.24118

Hatem Soliman, Roohi Ismail-Khan + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.24118

Copy DOI

Journal: Oncotarget	Publication Date: Jan 10, 2018
Citations: 37	License type: cc-by

Affiliation: Moffitt Cancer Center

Abstract

BackgroundIndoleamine 2, 3-dioxygenase is an enzyme that causes immunosuppression in tumors. Indoximod inhibits the indoleamine 2, 3-dioxygenase pathway and enhances immunologic responses to dendritic cell (DC) vaccines preclinically. Adenovirus p53 (Ad.p53) is used to generate DC vaccines against p53. A phase-1/2 trial of indoximod with Ad.p53-DC vaccine was conducted.Materials and MethodsThe phase-1 study combined 7 indoximod dose levels with < 6 Ad.p53-DC vaccinations every 2 weeks. Primary endpoints were maximum-tolerated dose in phase 1 and objective response in phase 2. Flow cytometry measured immune responses.ResultsThirty-nine patients were treated. In combination with Ad.p53-DC vaccine, the maximum-tolerated dose of indoximod was 1600 mg twice daily. Attributable toxicities were grade 1–2. Best response was stable disease in 4 patients. Immunologic responses were detected in 7 out of 23 evaluable patients. Median progression-free survival was 13.3 weeks (95% confidence interval, 12.97–21.85) and median overall survival was 20.71 weeks (95% confidence interval, 25.75–46.15). Nine out of 22 patients (40%) benefitted from chemotherapy after vaccination. Median overall survival in chemotherapy responders was 69.4 weeks (30.1–122.1).ConclusionsIndoximod 1600 mg twice daily with Ad.p53-DC was well tolerated. There may have been a chemosensitization effect. Future trials should explore combining this treatment with chemotherapy.

Highlights

The main physiologic function of indoximod is as the rate-limiting initial step in the breakdown of the essential amino acid tryptophan into various active metabolites, such as kynurenine and nicotinamide adenine dinucleotide
Future trials should explore combining this treatment with chemotherapy
The total number of patients who received at least 1 vaccine and 1 dose of indoximod was 39

Summary

Introduction

The main physiologic function of indoximod is as the rate-limiting initial step in the breakdown of the essential amino acid tryptophan into various active metabolites, such as kynurenine and nicotinamide adenine dinucleotide. The authors proposed that indoximod promoted a toleragenic state towards fetal antigens by depleting tryptophan, thereby inactivating the maternal effector T cells in the placenta. High levels of indoximod expression cause infiltrating effector T cells to arrest in G1, become anergic, and die www.impactjournals.com/oncotarget by apoptosis [2]. The depletion of tryptophan within the tumor causes an increase in the level of uncharged transfer RNAs and activation of the general control nonderepressible 2 kinase-mediated integrated stress response pathway in T cells [3]. Indoleamine 2, 3-dioxygenase is an enzyme that causes immunosuppression in tumors. Indoximod inhibits the indoleamine 2, 3-dioxygenase pathway and enhances immunologic responses to dendritic cell (DC) vaccines preclinically. A phase-1/2 trial of indoximod with Ad.p53-DC vaccine was conducted

Methods

Results

Conclusion