TY - JOUR
T1 - A blood-based immune marker for resistance to pembrolizumab in patients with metastatic urothelial cancer
AU - Rijnders, Maud
AU - Robbrecht, Debbie G. J.
AU - Oostvogels, Astrid A. M.
AU - van Brakel, Mandy
AU - Boormans, Joost L.
AU - Aarts, Maureen J. B.
AU - Balcioglu, Hayri E.
AU - Hamberg, Paul
AU - Voortman, Jens
AU - Westgeest, Hans M.
AU - Lolkema, Martijn P.
AU - de Wit, Ronald
AU - van der Veldt, Astrid A. M.
AU - Debets, Reno
N1 - Funding Information: Funding for this research was provided by MSD, The Netherlands. Funding Information: This research was funded by a grant from Merck Sharpe & Dome, Kenilworth, N.J., U.S.A., through MPL, RdW, and RD. We would like to thank Geert J.L.H. van Leenders (Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands) for assessing the PD-L1 combined positivity score for all patients. We thank all local principal investigators and the nurses of all contributing centers for their help with patient recruitment. We are particularly grateful to all participating patients and their families. Publisher Copyright: © 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - PD1 inhibition is effective in patients with metastatic urothelial cancer (mUC), yet a large fraction of patients does not respond. In this study, we aimed to identify a blood-based immune marker associated with non-response to facilitate patient selection for anti-PD1. To this end, we quantified 18 immune cell populations using multiplex flow cytometry in blood samples from 71 patients with mUC (as part of a biomarker discovery trial; NCT03263039, registration date 28-08-2017). Patients were classified as responder (ongoing complete or partial response, or stable disease; n = 25) or non-responder (progressive disease; n = 46) according to RECIST v1.1 at 6 months of treatment with pembrolizumab. We observed no differences in numbers of lymphocytes, T-cells, granulocytes, monocytes or their subsets between responders and non-responders at baseline. In contrast, analysis of ratios of immune cell populations revealed that a high mature neutrophil-to-T-cell ratio (MNTR) exclusively identified non-responders. In addition, the survival of patients with high versus low MNTR was poor: median overall survival (OS) 2.2 vs 8.9 months (hazard ratio (HR) 6.6; p < 0.00001), and median progression-free survival (PFS) 1.5 vs 5.2 months (HR 5.6; p < 0.0001). The associations with therapy response, OS, and PFS for the MNTR were stronger than for the classical neutrophil-to-lymphocyte ratio (HR for OS 3.5, and PFS 3) and the PD-L1 combined positivity score (HR for OS 1.9, and PFS 2.1). In conclusion, the MNTR distinctly and uniquely identified non-responders to treatment and may represent a novel pre-treatment blood-based immune metric to select patients with mUC for treatment with pembrolizumab.
AB - PD1 inhibition is effective in patients with metastatic urothelial cancer (mUC), yet a large fraction of patients does not respond. In this study, we aimed to identify a blood-based immune marker associated with non-response to facilitate patient selection for anti-PD1. To this end, we quantified 18 immune cell populations using multiplex flow cytometry in blood samples from 71 patients with mUC (as part of a biomarker discovery trial; NCT03263039, registration date 28-08-2017). Patients were classified as responder (ongoing complete or partial response, or stable disease; n = 25) or non-responder (progressive disease; n = 46) according to RECIST v1.1 at 6 months of treatment with pembrolizumab. We observed no differences in numbers of lymphocytes, T-cells, granulocytes, monocytes or their subsets between responders and non-responders at baseline. In contrast, analysis of ratios of immune cell populations revealed that a high mature neutrophil-to-T-cell ratio (MNTR) exclusively identified non-responders. In addition, the survival of patients with high versus low MNTR was poor: median overall survival (OS) 2.2 vs 8.9 months (hazard ratio (HR) 6.6; p < 0.00001), and median progression-free survival (PFS) 1.5 vs 5.2 months (HR 5.6; p < 0.0001). The associations with therapy response, OS, and PFS for the MNTR were stronger than for the classical neutrophil-to-lymphocyte ratio (HR for OS 3.5, and PFS 3) and the PD-L1 combined positivity score (HR for OS 1.9, and PFS 2.1). In conclusion, the MNTR distinctly and uniquely identified non-responders to treatment and may represent a novel pre-treatment blood-based immune metric to select patients with mUC for treatment with pembrolizumab.
KW - Biomarkers
KW - Cancer immunotherapy
KW - Flow cytometry
KW - Metastatic urothelial cancer
KW - PD1 inhibition
KW - Translational medical research
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85136949199&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35976415
U2 - https://doi.org/10.1007/s00262-022-03250-0
DO - https://doi.org/10.1007/s00262-022-03250-0
M3 - Article
C2 - 35976415
SN - 0340-7004
JO - Cancer Immunology and Immunotherapy
JF - Cancer Immunology and Immunotherapy
ER -