The kynurenine to tryptophan ratio as a prognostic tool for glioblastoma patients enrolling in immunotherapy - PubMed (original) (raw)

. 2015 Dec;22(12):1964-8.

doi: 10.1016/j.jocn.2015.06.018. Epub 2015 Aug 14.

Mahua Dey 2, Kristen L Lauing 1, Galina Gritsina 1, Rajwant Kaur 1, Rimas V Lukas 3, M Kelly Nicholas 4, Alfred W Rademaker 5, Carlos R Dostal 6, Robert H McCusker 7, Jeffrey J Raizer 8, Andrew T Parsa 9, Orin Bloch 9, Derek A Wainwright 10

Affiliations

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

Lijie Zhai et al. J Clin Neurosci. 2015 Dec.

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.

Copyright © 2015 Elsevier Ltd. All rights reserved.

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Conflict of interest statement

Conflicts of Interest/Disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Figures

Fig. 1

Fig. 1

Correlation of the kynurenine/tryptophan (Kyn/Trp) ratio with overall survival in glioblastoma multiforme (GBM) patients prior to enrolling in heat shock protein peptide complex-96 immunotherapy. Peripheral blood was collected from non-tumor bearing individuals as controls (C; squares), GBM patients prior to surgical resection (Presurg; upright triangles), or 48 hour (48h; upside down triangles) and ≥ 10 week (10w+; diamonds) postoperative resected GBM patients. The serum was analyzed for systemic (A) Trp, (B) Kyn and the (C) Kyn/Trp ratio. Each patient of the 10w+ GBM cohort was assigned a tracking number from 1–10 (A–D). (D) Overall survival of the 10w+ GBM patient cohort stratified by a ≥ 9.5 (red line) or ≤ 9.5 (blue line) Kyn/Trp ratio. The numbers in parentheses correspond to the assigned patient number. ***p < 0.0001.

Fig. 2

Fig. 2

Quantification of peripheral tryptophan (Trp) and kynurenine (Kyn) in presurgical patients with tumors of the central nervous system. Peripheral blood was collected from patients with primary glioblastoma multiforme (GBM; closed circle), recurrent GBM (closed square), meningioma Grade I (closed upright triangle), meningioma Grade II (closed upside down triangle), schwannoma Grade I (closed diamond), or central nervous infiltration of metastatic (Mets) melanoma (open circle), Mets lung (open square), Mets kidney (open upright triangle) and Mets breast (upside down triangle) cancer. The serum was analyzed for (A) Trp, (B) Kyn and the (C) Kyn/Trp ratio. (D) The frequency of patients from each cohort who possessed a high (≥ 9.5) Kyn/Trp ratio is plotted, and the total number of patients from each group is shown in parentheses above each respective bar.

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