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J Clin Neurosci. 2015 Dec;22(12):1964-8. doi: 10.1016/j.jocn.2015.06.018. Epub 2015 Aug 14.

The kynurenine to tryptophan ratio as a prognostic tool for glioblastoma patients enrolling in immunotherapy.

Author information

1
Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Tarry Bldg 2-703, 300 East Superior Street, Chicago, IL 60611, USA.
2
Department of Surgery, Section of Neurosurgery, University of Chicago, Chicago, IL, USA.
3
Department of Neurology, University of Chicago, Chicago, IL, USA.
4
Department of Neurology and Rehabilitation, The University of Illinois at Chicago, Chicago, IL, USA.
5
Department of Preventative Medicine, Biostatistics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
6
Neuroscience Program, The University of Illinois at Urbana-Champaign, Urbana, IL, USA.
7
Neuroscience Program, The University of Illinois at Urbana-Champaign, Urbana, IL, USA; Department of Animal Sciences, The University of Illinois at Urbana-Champaign, Urbana, IL, USA.
8
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
9
Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Tarry Bldg 2-703, 300 East Superior Street, Chicago, IL 60611, USA; Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
10
Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Tarry Bldg 2-703, 300 East Superior Street, Chicago, IL 60611, USA. Electronic address: derekwainwright@northwestern.edu.

Abstract

We hypothesized that peripheral tryptophan (Trp) and/or kynurenine (Kyn) levels would provide prognostic value for physicians planning to enroll glioblastoma multiforme (GBM) patients in immunotherapy. GBM is the most common form of malignant glioma in adults. Despite aggressive surgical resection, irradiation and chemotherapy, patients with GBM have a median survival of only 14.6 months after diagnosis. This poor outcome has led to the search for more effective treatments, including immunotherapy. However, the identification of parameters that proactively stratify GBM patients who have the potential for therapeutic benefit has been challenging. Given recent observations demonstrating high indoleamine 2,3 dioxygenase 1 (IDO1) expression in GBM, the immunosuppressive impact of IDO1-mediated Trp catabolism, as well as active transport of Trp and the IDO1-downstream Trp catabolite, Kyn, across the blood brain barrier, we hypothesized that peripheral blood analysis of this pathway would provide diagnostic utility. When comparing individuals without tumors to GBM patients prior to surgical resection, or at the 48 hour (48 h) and ⩾10 week (10 w+) postoperative time points, Trp levels were significantly decreased (p<0.0002). Similarly, Kyn levels were decreased in the pre- and 48 h postoperative GBM patients (p<0.0001), while there was no difference between individuals without tumors and 10 w+ GBM patients. Interestingly, those 10 w+ patients with a high Kyn/Trp ratio (⩾9.5) had a mean overall survival (OS) of 23.6 ± a standard error of 6.8 months, compared to an OS of 38.7 ± 4.9 months for patients with lower Kyn/Trp values. Since the 10 w+ blood draw and analyses occurred prior to patient enrollment in the heat shock protein peptide complex-96 clinical trial, these novel data suggest that the late Kyn/Trp index may be a relevant clinical benchmark, providing prognostic value for GBM patients who are enrolled in immunotherapeutic regimens.

KEYWORDS:

Brain tumor; Diagnostic; Glioblastoma multiforme; Immunosuppression; Kynurenine; Metabolism; Tryptophan

PMID:
26279502
PMCID:
PMC4548799
DOI:
10.1016/j.jocn.2015.06.018
[Indexed for MEDLINE]
Free PMC Article

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