Kevin Tyan1,2, Joanna Baginska2, Martha Brainard2, Anita Giobbie-Hurder3, Mariano Severgnini2, Michael Manos2, Rizwan Haq1,2, Elizabeth I Buchbinder1,2, Patrick A Ott1,2, F Stephen Hodi1,2, Osama E Rahma4,5. 1. Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA. 2. Center for Immuno-Oncology, Department of Medical Oncology, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA. 3. Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA. 4. Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA. Osamae_rahma@DFCI.harvard.edu. 5. Center for Immuno-Oncology, Department of Medical Oncology, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA. Osamae_rahma@DFCI.harvard.edu.
Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs), most of which are treated with corticosteroids despite evidence suggesting that corticosteroids may blunt antitumor efficacy. We sought to identify cytokine changes that correlate with irAEs and study the impact of corticosteroid treatment on cytokine levels. METHODS: We analyzed expression of 34 cytokines in 52 melanoma patients who developed irAEs during therapy with ICIs. Luminex serum assay was performed at baseline, 1, 2, and 3 months after starting ICI. Baseline cytokine levels and longitudinal log2 fold-change was compared with incidence and grade of irAEs. Cytokine patterns were compared between patients based on development of irAEs and steroid treatment. RESULTS: There were no differences in baseline cytokine levels between patients who developed grade 1-2 irAEs (N = 28) vs. grade 3-4 irAEs (N = 24). Dermatitis patients (N = 8) had significantly higher baseline Ang-1 (p = 0.006) and CD40L (p = 0.005). Pneumonitis patients (N = 4) had significantly higher baseline IL-17 (p = 0.009). Colitis patients (N = 8) had a trend toward decreased GCSF (p = 0.08). Through Spearman's correlation analysis, patients who developed irAEs without receiving corticosteroids (N = 23) exhibited harmonization of cytokine fold-change, with 0/276 pairwise comparisons demonstrating significant divergence. In contrast, corticosteroid treatment in patients with irAEs (N = 15) altered fold-change to a discordant pattern (42/276 diverged, 15.2%). This discordant cytokine pattern in patients receiving corticosteroids is similar to the cytokine pattern in patients who did not develop irAEs (N = 8) during the longitudinal profiling period (41/276, 14.9%). CONCLUSIONS: Baseline levels of certain cytokines correlate with specific irAEs in melanoma patients receiving ICIs. irAEs drive a concordant pattern of cytokine fold-change, which is disrupted by corticosteroid treatment.
BACKGROUND: Immune checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs), most of which are treated with corticosteroids despite evidence suggesting that corticosteroids may blunt antitumor efficacy. We sought to identify cytokine changes that correlate with irAEs and study the impact of corticosteroid treatment on cytokine levels. METHODS: We analyzed expression of 34 cytokines in 52 melanomapatients who developed irAEs during therapy with ICIs. Luminex serum assay was performed at baseline, 1, 2, and 3 months after starting ICI. Baseline cytokine levels and longitudinal log2 fold-change was compared with incidence and grade of irAEs. Cytokine patterns were compared between patients based on development of irAEs and steroid treatment. RESULTS: There were no differences in baseline cytokine levels between patients who developed grade 1-2 irAEs (N = 28) vs. grade 3-4 irAEs (N = 24). Dermatitispatients (N = 8) had significantly higher baseline Ang-1 (p = 0.006) and CD40L (p = 0.005). Pneumonitis patients (N = 4) had significantly higher baseline IL-17 (p = 0.009). Colitispatients (N = 8) had a trend toward decreased GCSF (p = 0.08). Through Spearman's correlation analysis, patients who developed irAEs without receiving corticosteroids (N = 23) exhibited harmonization of cytokine fold-change, with 0/276 pairwise comparisons demonstrating significant divergence. In contrast, corticosteroid treatment in patients with irAEs (N = 15) altered fold-change to a discordant pattern (42/276 diverged, 15.2%). This discordant cytokine pattern in patients receiving corticosteroids is similar to the cytokine pattern in patients who did not develop irAEs (N = 8) during the longitudinal profiling period (41/276, 14.9%). CONCLUSIONS: Baseline levels of certain cytokines correlate with specific irAEs in melanomapatients receiving ICIs. irAEs drive a concordant pattern of cytokine fold-change, which is disrupted by corticosteroid treatment.
Authors: Alexander T Faje; Donald Lawrence; Keith Flaherty; Christine Freedman; Riley Fadden; Krista Rubin; Justine Cohen; Ryan J Sullivan Journal: Cancer Date: 2018-07-05 Impact factor: 6.860
Authors: Kathryn C Arbour; Laura Mezquita; Niamh Long; Hira Rizvi; Edouard Auclin; Andy Ni; Gala Martínez-Bernal; Roberto Ferrara; W Victoria Lai; Lizza E L Hendriks; Joshua K Sabari; Caroline Caramella; Andrew J Plodkowski; Darragh Halpenny; Jamie E Chaft; David Planchard; Gregory J Riely; Benjamin Besse; Matthew D Hellmann Journal: J Clin Oncol Date: 2018-08-20 Impact factor: 44.544
Authors: Giovanni Fucà; Giulia Galli; Marta Poggi; Giuseppe Lo Russo; Claudia Proto; Martina Imbimbo; Roberto Ferrara; Nicoletta Zilembo; Monica Ganzinelli; Antonio Sica; Valter Torri; Mario Paolo Colombo; Claudio Vernieri; Andrea Balsari; Filippo de Braud; Marina Chiara Garassino; Diego Signorelli Journal: ESMO Open Date: 2019-02-27
Authors: Ahmad A Tarhini; Haris Zahoor; Yan Lin; Usha Malhotra; Cindy Sander; Lisa H Butterfield; John M Kirkwood Journal: J Immunother Cancer Date: 2015-09-15 Impact factor: 13.751
Authors: Shaheen Khan; Saad A Khan; Xin Luo; Farjana J Fattah; Jessica Saltarski; Yvonne Gloria-McCutchen; Rong Lu; Yang Xie; Quan Li; Edward Wakeland; David E Gerber Journal: Br J Cancer Date: 2018-10-31 Impact factor: 7.640
Authors: Vincent T Ho; Haesook T Kim; Jennifer Brock; Ilene Galinsky; Heather Daley; Carol Reynolds; Augustine Weber; Olga Pozdnyakova; Mariano Severgnini; Sarah Nikiforow; Corey Cutler; John Koreth; Edwin P Alyea; Joseph H Antin; Mahasweta Gooptu; Rizwan Romee; Roman Shapiro; Yi-Bin Chen; Jacalyn Rosenblatt; David Avigan; F Stephen Hodi; Glenn Dranoff; Catherine J Wu; Jerome Ritz; Robert J Soiffer Journal: Blood Adv Date: 2022-04-12