Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1 based immunotherapy

Su Yin Lim, Jenny H. Lee, Tuba Nur Gide, Alexander M. Menzies, Alexander Guminski, Matteo S. Carlino, Edmond Breen, Jean Y. H. Yang, Shila Ghazanfar, Richard F. Kefford, Richard A. Scolyer, Georgina V. Long, Helen Rizos

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose: Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity.

Experimental Design: The expression of 65 cytokines was profiled longitudinally in 98 patients with melanoma treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high-dose steroids.

Results: Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95% confidence interval (CI), 0.51–0.84; P = 0.037] and 0.70 at EDT (95% CI, 0.55–0.85; P = 0.017) using ROC analysis.

Conclusions: The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1a, IL2, and IFNα2, may help in the early management of severe, potentially life-threatening immune-related toxicity.
LanguageEnglish
Pages1557-1563
Number of pages7
JournalClinical Cancer Research
Volume25
Issue number5
Early online date8 Nov 2018
DOIs
Publication statusPublished - Mar 2019

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Immunotherapy
Melanoma
Cytokines
Confidence Intervals
Therapeutics
ROC Curve
Area Under Curve
Interleukin-2
Research Design
Biomarkers
Steroids
Survival

Cite this

Lim, Su Yin ; Lee, Jenny H. ; Nur Gide, Tuba ; Menzies, Alexander M. ; Guminski, Alexander ; Carlino, Matteo S. ; Breen, Edmond ; Yang, Jean Y. H. ; Ghazanfar, Shila ; Kefford, Richard F. ; Scolyer, Richard A. ; Long, Georgina V. ; Rizos, Helen. / Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1 based immunotherapy. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 5. pp. 1557-1563.
@article{a4ea650b3c2b4ea496817679076af759,
title = "Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1 based immunotherapy",
abstract = "Purpose: Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity.Experimental Design: The expression of 65 cytokines was profiled longitudinally in 98 patients with melanoma treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high-dose steroids.Results: Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95{\%} confidence interval (CI), 0.51–0.84; P = 0.037] and 0.70 at EDT (95{\%} CI, 0.55–0.85; P = 0.017) using ROC analysis.Conclusions: The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1a, IL2, and IFNα2, may help in the early management of severe, potentially life-threatening immune-related toxicity.",
author = "Lim, {Su Yin} and Lee, {Jenny H.} and {Nur Gide}, Tuba and Menzies, {Alexander M.} and Alexander Guminski and Carlino, {Matteo S.} and Edmond Breen and Yang, {Jean Y. H.} and Shila Ghazanfar and Kefford, {Richard F.} and Scolyer, {Richard A.} and Long, {Georgina V.} and Helen Rizos",
year = "2019",
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doi = "10.1158/1078-0432.CCR-18-2795",
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Lim, SY, Lee, JH, Nur Gide, T, Menzies, AM, Guminski, A, Carlino, MS, Breen, E, Yang, JYH, Ghazanfar, S, Kefford, RF, Scolyer, RA, Long, GV & Rizos, H 2019, 'Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1 based immunotherapy', Clinical Cancer Research, vol. 25, no. 5, pp. 1557-1563. https://doi.org/10.1158/1078-0432.CCR-18-2795

Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1 based immunotherapy. / Lim, Su Yin; Lee, Jenny H.; Nur Gide, Tuba; Menzies, Alexander M.; Guminski, Alexander; Carlino, Matteo S.; Breen, Edmond; Yang, Jean Y. H.; Ghazanfar, Shila; Kefford, Richard F.; Scolyer, Richard A.; Long, Georgina V.; Rizos, Helen.

In: Clinical Cancer Research, Vol. 25, No. 5, 03.2019, p. 1557-1563.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1 based immunotherapy

AU - Lim, Su Yin

AU - Lee, Jenny H.

AU - Nur Gide, Tuba

AU - Menzies, Alexander M.

AU - Guminski, Alexander

AU - Carlino, Matteo S.

AU - Breen, Edmond

AU - Yang, Jean Y. H.

AU - Ghazanfar, Shila

AU - Kefford, Richard F.

AU - Scolyer, Richard A.

AU - Long, Georgina V.

AU - Rizos, Helen

PY - 2019/3

Y1 - 2019/3

N2 - Purpose: Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity.Experimental Design: The expression of 65 cytokines was profiled longitudinally in 98 patients with melanoma treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high-dose steroids.Results: Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95% confidence interval (CI), 0.51–0.84; P = 0.037] and 0.70 at EDT (95% CI, 0.55–0.85; P = 0.017) using ROC analysis.Conclusions: The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1a, IL2, and IFNα2, may help in the early management of severe, potentially life-threatening immune-related toxicity.

AB - Purpose: Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity.Experimental Design: The expression of 65 cytokines was profiled longitudinally in 98 patients with melanoma treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high-dose steroids.Results: Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline (PRE) and early during treatment (EDT). The expression of these 11 cytokines was integrated into a single toxicity score, the CYTOX (cytokine toxicity) score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. The AUC for the CYTOX score in the validation cohort was 0.68 at PRE [95% confidence interval (CI), 0.51–0.84; P = 0.037] and 0.70 at EDT (95% CI, 0.55–0.85; P = 0.017) using ROC analysis.Conclusions: The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes proinflammatory cytokines such as IL1a, IL2, and IFNα2, may help in the early management of severe, potentially life-threatening immune-related toxicity.

UR - http://purl.org/au-research/grants/nhmrc/1130423

UR - http://purl.org/au-research/grants/nhmrc/1093017

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U2 - 10.1158/1078-0432.CCR-18-2795

DO - 10.1158/1078-0432.CCR-18-2795

M3 - Article

VL - 25

SP - 1557

EP - 1563

JO - Clinical Cancer Research

T2 - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 5

ER -