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:
Funding for this research was provided by MSD, The
Netherlands.
© 2022. The Author(s).
PY - 2023/3
Y1 - 2023/3
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.
UR - http://www.scopus.com/inward/record.url?scp=85136949199&partnerID=8YFLogxK
U2 - 10.1007/s00262-022-03250-0
DO - 10.1007/s00262-022-03250-0
M3 - Article
C2 - 35976415
SN - 0340-7004
VL - 72
SP - 759
EP - 767
JO - Cancer Immunology Immunotherapy
JF - Cancer Immunology Immunotherapy
IS - 3
ER -
