Development of a Flow Cytometry Assay to Predict Immune Checkpoint Blockade-Related Complications
Hannah-Lou Schilling,Gunther Glehr,Michael Kapinsky,Norbert Ahrens,Paloma Riquelme,Laura Cordero,F Bitterer,Hans J. Schlitt,Edward K. Geissler,Sebastian Haferkamp,James A. Hutchinson,Katharina Kronenberg +11 more
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TLDR
In this article, a 10-color flow cytometry panel was developed and validated for reliably quantifying CD4+ TEM cells and other biomarkers of irAE risk in peripheral blood samples.Abstract:
Treatment of advanced melanoma with combined immune checkpoint inhibitor (ICI) therapy is complicated in up to 50 % of cases by immune-related adverse events (irAE) that commonly include hepatitis, colitis and skin reactions. We previously reported that pre-therapy expansion of cytomegalovirus (CMV)-reactive CD4+ effector memory T cells (TEM) predicts ICI-related hepatitis in a subset of patients with Stage IV melanoma given αPD-1 and αCTLA-4. Here, we develop and validate a 10-color flow cytometry panel for reliably quantifying CD4+ TEM cells and other biomarkers of irAE risk in peripheral blood samples. Compared to previous methods, our new panel performs equally well in measuring CD4+ TEM cells (agreement = 98 %) and is superior in resolving CD4+ CD197+ CD45RA- central memory T cells (TCM) from CD4+ CD197+ CD45RA+ naive T cells (Tnaive). It also enables us to precisely quantify CD14+ monocytes (CV = 6.6 %). Our new “monocyte and T cell” (MoT) assay predicts immune-related hepatitis with a positive predictive value (PPV) of 83 % and negative predictive value (NPV) of 80 %. Our essential improvements open the possibility of sharing our predictive methods with other clinical centers. Furthermore, condensing measurements of monocyte and memory T cell subsets into a single assay simplifies our workflows and facilitates computational analyses.read more
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External validation of biomarkers for immune-related adverse events after immune checkpoint inhibition
Gunther Glehr,Paloma Riquelme,Jordi Yang Zhou,L Cordero,Hannah-Lou Schilling,Michael Kapinsky,Hans J. Schlitt,Edward K. Geissler,Ralph Burkhardt,Barbara Schmidt,Sebastian Haferkamp,James A. Hutchinson,Katharina Kronenberg +12 more
TL;DR: Externally validate the performance of 59 previously reported markers of irAE risk in a new cohort of 110 patients receiving Nivolumab and Ipilimumab therapy, finding that alone or combined, the discriminatory value of these routine clinical parameters and flow cytometry biomarkers was poor.
Journal ArticleDOI
Advanced Immune Cell Profiling by Multiparameter Flow Cytometry in Humanized Patient-Derived Tumor Mice
Christina Bruß,Kerstin Kellner,Olaf Ortmann,Stephan Seitz,Gero Brockhoff,James A. Hutchinson,Anja K. Wege +6 more
TL;DR: Multicolor flow cytometry was applied to characterize immune cell subsets in the spleen of humanized mice transplanted with patient-derived breast cancer tissues to contribute to a better understanding of immune-oncologic processes.
Journal ArticleDOI
Prediction of immune checkpoint blockade‐related hepatitis in metastatic melanoma patients
TL;DR: A subset of patients with metastatic melanoma that are predisposed to hepatitis after combined PD‐1 and CTLA‐4 blockade is identified, characterized by pre‐treatment expansion of effector memory CD4+ T cells (TEM cells) in blood, which is a reliable biomarker of hepatitis risk.
Journal ArticleDOI
Vorhersage von Immuncheckpoint‐Inhibitor‐bedingter Hepatitis bei Patienten mit metastasiertem Melanom
TL;DR: In this article , a Gruppe von Tumorerkrankungen is gelungen, Patienten mit metastasiertem Melanom zu identifizieren, die eine erhöhtes Risiko haben, eine immunvermittelte Hepatitis zu entwickeln.
Posted ContentDOI
Restricting datasets to classifiable samples augments discovery of immune disease markers
TL;DR: In this article , the authors introduce dataset restriction, a procedure that splits datasets into classifiable and unclassifiable samples, and apply it to synthetic flow cytometry data to find new markers of immune-related adverse event risk after immunotherapy.
References
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Jedd D. Wolchok,Vanna Chiarion-Sileni,Rene Gonzalez,Piotr Rutkowski,Jean-Jacques Grob,C. Lance Cowey,Christopher D. Lao,John Wagstaff,Dirk Schadendorf,Pier Francesco Ferrucci,Michael Smylie,Reinhard Dummer,Andrew F. Hill,David Hogg,John B. A. G. Haanen,Matteo S. Carlino,Oliver Bechter,Michele Maio,Ivan Marquez-Rodas,Massimo Guidoboni,Grant A. McArthur,Céleste Lebbé,Paolo A. Ascierto,Georgina V. Long,Jonathan Cebon,Jeffrey A. Sosman,Michael A. Postow,Margaret K. Callahan,Dana Walker,Linda Rollin,Rafia Bhore,F. Stephen Hodi,James Larkin,James Larkin +33 more
TL;DR: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with n ivolumAB alone than with ipil optimumab alone.
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Immune-Related Adverse Events Associated with Immune Checkpoint Blockade
TL;DR: The wide range of immune-related adverse effects associated with immune checkpoint blockade can complicate this effective therapy and limit its use in patients with cancer.
Journal ArticleDOI
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma
Michael A. Postow,Jason Chesney,Anna C. Pavlick,Caroline Robert,Kenneth F. Grossmann,David F. McDermott,Gerald P. Linette,Nicolas Meyer,Jeffrey K. Giguere,Sanjiv S. Agarwala,Montaser Shaheen,Marc S. Ernstoff,David R. Minor,April K.S. Salama,Matthew H. Taylor,Patrick A. Ott,Linda Rollin,Christine Horak,Paul Gagnier,Jedd D. Wolchok,F. Stephen Hodi +20 more
TL;DR: The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipILimumab monotherapy.