title: Complement-Regulatory Proteins CFHR1 and CFHR3 and Patient Response to Anti-CD20 Monoclonal Antibody Therapy.
abstract: Purpose:Anti-CD20 mAb therapies, including rituximab and obinutuzumab (GA101), are common treatments for follicular lymphoma. In an effort to better understand the role of complement in mAb action, we recently performed germline SNP profiling on 142 follicular lymphoma patients and found rs3766404 genotype correlated with patient response to rituximab. To assess the role of three SNP-associated complement-regulatory proteins (CFH, CFHR1, and CFHR3) in clinical response to anti-CD20 mAb, we studied two cohorts of patients treated with anti-CD20 mAb.Experimental Design:Cohorts included the Iowa/Mayo Lymphoma SPORE observational cohort of subjects with a new diagnosis of follicular lymphoma treated with rituximab and the GAUSS prospective randomized trial cohort of follicular lymphoma subjects randomized to receive single-agent rituximab or obinutuzumab. Circulating protein expression was measured for CFH, CFHR1, and CFHR3 and correlated to clinical outcome.Results:rs3766404 genotype correlated with expression of the related downstream genesCFHR1andCFHR3Loss of CFHR1 expression correlated with inferior patient outcome in the observational cohort, but not in the GAUSS cohort. Loss of CFHR3 correlated with superior event-free survival in GAUSS subjects treated with obinutuzumab, but not rituximab.Conclusions:We conclude that the relationship between complement-regulatory proteins CFHR1 and CFHR3 and response to anti-CD20 mAb therapy varies based on the specific anti-CD20 mAb used. We propose that CFHR3 is a candidate biomarker for obinutuzumab response. Further studies are needed to validate these findings and to better understand how complement pathways and complement-regulatory proteins impact on the efficacy of anti-CD20 mAb therapy.Clin Cancer Res; 23(4); 954-61. ©2016 AACR.
authors.affiliation: Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Rogers
authors.affiliation: Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Mott
authors.affiliation: Department of Biostatistics, The University of Iowa, Iowa City, Iowa.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.affiliation: Department of Internal Medicine, The University of Iowa, Iowa City, Iowa.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Link
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Deniz
authors.initials: D
authors.lastname: Sahin
authors.affiliation: Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa. george-weiner@uiowa.edu.
authors.forename: George J
authors.initials: GJ
authors.lastname: Weiner
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D018951:Antigens, CD20 / Q000235:genetics* / Q000276:immunology; D054316:Biomarkers, Pharmacological / Q000097:blood; D001798:Blood Proteins / Q000235:genetics*; D003180:Complement C3b Inactivator Proteins / Q000235:genetics*; D003165:Complement System Proteins / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005838:Genotype; D006801:Humans; D008224:Lymphoma, Follicular / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000069283:Rituximab / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D054316:Biomarkers, Pharmacological; D001798:Blood Proteins; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins; D000069283:Rituximab; D003165:Complement System Proteins; C543332:obinutuzumab