title: Fc-gamma receptor polymorphisms as predictive and prognostic factors in patients receiving oncolytic adenovirus treatment.
abstract: BACKGROUND
  Oncolytic viruses have shown potential as cancer therapeutics, but not all patients seem to benefit from therapy. Polymorphisms in Fc gamma receptors (FcgRs) lead to altered binding affinity of IgG between the receptor allotypes and therefore contribute to differences in immune defense mechanisms. Associations have been identified between FcgR polymorphisms and responsiveness to different immunotherapies. Taken together with the increasing understanding that immunological factors might determine the efficacy of oncolytic virotherapy we studied whether FcgR polymorphisms would have prognostic and/or predictive significance in the context of oncolytic adenovirus treatments.
  
  
  METHODS
  235 patients with advanced solid tumors were genotyped for two FcgR polymorphisms, FcgRIIa-H131R (rs1801274) and FcgRIIIa-V158F (rs396991), using TaqMan based qPCR. The genotypes were correlated with patient survival and tumor imaging data.
  
  
  RESULTS
  In patients treated with oncolytic adenoviruses, overall survival was significantly shorter if the patient had an FcgRIIIa-VV/ FcgRIIa-HR (VVHR) genotype combination (P = 0,032). In contrast, patients with FFHR and FFRR genotypes had significantly longer overall survival (P = 0,004 and P = 0,006, respectively) if they were treated with GM-CSF-armed adenovirus in comparison to other viruses. Treatment of these patients with unarmed virus correlated with shorter survival (P < 0,0005 and P = 0,016, respectively). Treating FFHH individuals with CD40L-armed virus resulted in longer survival than treatment with other viruses (P = 0,047).
  
  
  CONCLUSIONS
  Our data are compatible with the hypothesis that individual differences in effector cell functions, such as NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and tumor antigen presentation by APCs caused by polymorphisms in FcgRs could play role in the effectiveness of oncolytic virotherapies. If confirmed in larger populations, FcgR polymorphisms could have potential as prognostic and predictive biomarkers for oncolytic adenovirus therapies to enable better selection of patients for clinical trials. Also, putative associations between genotypes, different viruses and survival implicate potentially important mechanistic issues.
authors: Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Haartmaninkatu 3, Helsinki 00290, Finland.
authors: Mari
authors: M
authors: Hirvinen
authors: Raita
authors: R
authors: Heiskanen
authors: Minna
authors: M
authors: Oksanen
authors: Saila
authors: S
authors: Pesonen
authors: Ilkka
authors: I
authors: Liikanen
authors: Timo
authors: T
authors: Joensuu
authors: Anna
authors: A
authors: Kanerva
authors: Vincenzo
authors: V
authors: Cerullo
authors: Akseli
authors: A
authors: Hemminki
mesh_terms: D000256:Adenoviridae / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D050130:Oncolytic Virotherapy; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D017452:Receptors, IgG / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C445323:FCGR2A protein, human; C496124:FCGR3A protein, human; D017452:Receptors, IgG
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