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Introduction: We sought to determine whether IL-2 stimulated increases in peripheral IFN-g plasma concentrations would be associated with increases in IL-6 plasma levels and decreases in FACT/GOG-Ntx Scores
Methods: After signing informed consent, patients with Stage III-IV malignant melanoma were recruited. Prior to, during, and after IL-2 administration we measured plasma concentrations of IFN-g, neurobehavioral symptoms, cognitive function, and tolerance of IL-2 treatment. The Friedman test, Wilcoxon signed-rank test and Spearman’s correlation were used in the analysis.
Results: IFN-g levels were undetectable until about two hours post injection. The neurotoxicity scores and IFN-g levels correlate during cycle 4 and the Ntx scores reach a low at the same time point that the IFN-g levels reach their peak.
Conclusion: Our findings support our proposed model but further analysis of levels of TNF-a, tryptophan and quinolinic acid are still needed. Recruitment of more patients will also allow for more accurate and visible correlations
Cytokines, a vast family of regulatory proteins involved in signaling within the immune system, are critical for activation of host immune defense.1
The cytokine interleukin-2 (IL-2) is used as an antineoplastic regimen in patients with malignant melanoma and has been shown to induce neurobehavioral symptoms.1
The cytokine interleukin-6 is released by both the B and T cells and is involved in many immune system processes including inflammation, neuronal differentiation, and bone loss.2
The cytokine IFN-g activates macrophages and is associated with tumor regression.3
IFNg activates the enzyme indoleamine dioxygenase which degrades tryptophan.3
This consequent tryptophan depletion is believed to play a role the neurotoxic and neuropsychiatric side effects of cytokine treatment.3
Eligible subjects received treatment with either escitalopram or placebo 1-2 weeks prior to beginning intravenous IL-2 therapy [720,000 units/kg Q8 hours X 5 days (1 cycle) every 3 weeks X 4 cycles]. Blood draws were performed at regular intervals prior to and during each IL-2 cycle.
Plasma IFN-g levels were measured via enzyme linked immunoassay (R&D Systems Quantikine). The standard curve was 15.6 pg/mL -1000pg/mL scale and the minimum detectable level of IFN-g was < 8.0pg/mL
IL-2 treatment adherence was evaluated according to the patient’s medical records.
The Functional Assessment of Cancer Therapy Neurotoxicity sub-scale
(range 0-44) was used to determine self-rated neurotoxic symptoms.4
Biostatistical Methods
Descriptive statistics were used to determine applicable statistical methods.
Differences between time points were assessed using the Friedman test and the Wilcoxon signed-rank test, both non-parametric statistical methods.
Relationships between immune system activation, assessments of neurobehavioral symptoms, and IL-2 therapy cycle were determined via Spearman’s correlation.
Of the 21 patients who provided informed consent, 17 patients were enrolled; 41% of patients completed all four cycles of IL-2 treatment.
The mean number of cycles completed were 3 cycles (p= 0.50
The Freidman test showed no significant change in IFN-g levels between the post injection data sets for each cycle .
IFN-g levels significantly increased for the first time cycle 1 day 2 (z=-2.27, p<0.05).
The peak IFN-g level occurred at cycle 4 day 3 (mean=114.56 pg/mL).
Friedman Test revealed differences in IL-6 plasma concentrations during IL-2 treatment (p=0.02).
IL-6 is significantly increased for the first time during cycle 1 day1 post IL-2 injection (9 am) (mean=95.82 pg/mL) (p<0.01).
IL-6 and IFN-g levels are correlated on cycle 4 day 2 (r=0.99, p<0.01) and on cycle 4 day 3 (r=0.99, p<0.01).
Baseline and post treatment Ntx average score was 42.
The Freidman test showed no significant change in Neurotoxicity scores
The lowest neurotoxicity score was cycle 4 day 3 (mean= 39.8) indicating highest neurotoxicity.
Regardless of timepoint, extreme neurotoxicity was not observed.
IFN-g negatively correlated with the neurotoxicity scores on cycle 4 day 1
(r=-.852, p<0.05) and IL-6 negatively correlated neurotoxicity scores on cycle 4 day 2 (r=-0.994 , p<0.01) and cycle 4 day 3 (r=-0.925, p<0.05)
IFN-g levels were undetectable until two hours post Il-2 injection which supports our hypothesis that IL-2 treatment will stimulate the production of IFN-g.
IFN-g levels return to undetectable levels between each cycle of IL-2.
The peak IFN-g level occurs during cycle 4 indicating a delay between initiation of IL-2 treatment and maximum IFN-g production.
Strong correlations between IFN-g and IL-6 during cycle 4 support our model of IL-2 induced immune system activation.
The neurotoxicity scores IFN-g levels correlate during cycle 4 also supporting our proposed model.
Future Directions
Analysis of levels of TNFa, tryptophan, and quinolinic acid will further the development of our proposed model.
Further analysis of the Functional Assessment of Cancer Therapy will determine immune system activation’s role in the quality of life of the patients.
Additional recruitment will allow for more in depth analysis of immune and behavioral measures.
Unblinding of the treatment group of study participants will allow determination of the effects of escitalopram pretreatment on the neurotoxic and neurobehavioral effects of IL-2 treatment.
This material is based upon work supported by the Howard Hughes Medical Institute under Grant No. 52005873, National Institutes of Mental Health Grant R01MH71580 to Dominique L. Musselman, and an Atlanta Clinical and Translational Science Institute award.
1. Capruronn L, ert al. Association between immune activation and early depressive symptoms in cancer patients treated with interleuken-2-based therapy. Psychoneuroendocrino 2001, 26: 797-808.
2. O’Dell W. Pathways: IL-6 signaling pathway. Biocarta.com.
3. Menkes DB, et al. Interferons, serotonin and neurotoxicity, Psychol Med, 2000; 30:259-268.
4. Calhoun EA, et al. Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group—Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 2003, 13: 741-748.
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