The phase II NIVOREN GETUG-AFU 26 study reported safety and efficacy of nivolumab in patients with metastatic clear cell renal cell carcinoma (m-ccRCC) in a 'real-world setting'. We conducted a translational-research program to determine whether specific circulating immune-cell populations and/or soluble factors at baseline were predictive of clinical outcomes in patients with m-ccRCC treated with nivolumab within the NIVOREN study.
Absolute numbers of 106 circulating immune-cell populations were prospectively analyzed in patients treated at a single institution within the NIVOREN trial with available fresh-whole-blood, using dry formulation panels for multicolor flow cytometry. In addition, a panel of 14 predefined soluble factors was quantified for each baseline plasma sample using the Meso-Scale-Discovery immunoassay. The remaining patients with available plasma sample were used as a validation cohort for the soluble factor quantification analysis. Tumor immune microenvironment characterization of all patients included in the translational program of the study was available. The association of blood and tissue-based biomarkers, with overall survival (OS), progression-free survival (PFS) and response was analyzed.
Among the 44 patients, baseline unswitched memory B cells (NSwM B cells) were enriched in responders (p=0.006) and associated with improved OS (HR=0.08, p=0.002) and PFS (HR=0.54, p=0.048). Responders were enriched in circulating T follicular helper (Tfh) (p=0.027) and tertiary lymphoid structures (TLS) (p=0.043). Circulating NSwM B cells positively correlated with Tfh (r=0.70, p<0.001). Circulating NSwM B cells correlated positively with TLS and CD20 +B cells at the tumor center (r=0.59, p=0.044, and r=0.52, p=0.033) and inversely correlated with BCA-1/CXCL13 and BAFF (r=-0.55 and r=-0.42, p<0.001). Tfh cells also inversely correlated with BCA-1/CXCL13 (r=-0.61, p<0.001). IL-6, BCA-1/CXCL13 and BAFF significantly associated with worse OS in the discovery (n=40) and validation cohorts (n=313).
We report the first fresh blood immune-monitoring of patients with m-ccRCC treated with nivolumab. Baseline blood concentration of NSwM B cells was associated to response, PFS and OS in patients with m-ccRCC treated with nivolumab. BCA-1/CXCL13 and BAFF, inversely correlated to NSwM B cells, were both associated with worse OS in discovery and validation cohorts. Our data confirms a role for B cell subsets in the response to immune checkpoint blockade therapy in patients with m-ccRCC. Further studies are needed to confirm these findings.
Journal for immunotherapy of cancer. 2022 May [Epub]
Lucia Carril-Ajuria, Aude Desnoyer, Maxime Meylan, Cécile Dalban, Marie Naigeon, Lydie Cassard, Yann Vano, Nathalie Rioux-Leclercq, Salem Chouaib, Benoit Beuselinck, Sylvie Chabaud, Janice Barros-Monteiro, Antoine Bougoüin, Guillaume Lacroix, Irelka Colina-Moreno, Florence Tantot, Lisa Boselli, Caroline De Oliveira, Wolf Herve Fridman, Bernard Escudier, Catherine Sautes-Fridman, Laurence Albiges, Nathalie Chaput-Gras
Department of Cancer Medicine, Institut Gustave-Roussy, Villejuif, France., Laboratory for Immunomonitoring in Oncology, Institut Gustave-Roussy, Villejuif, France., Centre de Recherche des Cordeliers, Inserm UMR S1138, Paris, France., Department of Biostatistics, Centre Leon Bernard, Lyon, France., Faculté de Pharmacie, Université Paris-Saclay, Chatenay-Malabray, France., Service Anatomie Etcytologie Pathologiques, CHU, Université de Rennes, Universite de Rennes 1, Rennes, France., Department of Immunology, Gustave Roussy Institute, Villejuif, France., Leuven Cancer Institute, Leuven, Belgium., Translational Research, UNICANCER, Paris, France., GETUG group, Unicancer, Paris, France., Laboratory for Immunomonitoring in Oncology, Institut Gustave-Roussy, Villejuif, France .