Abstract
BackgroundOncolytic 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.Methods235 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.ResultsIn 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).ConclusionsOur 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.
Highlights
Oncolytic viruses have shown potential as cancer therapeutics, but not all patients seem to benefit from therapy
Genotypic frequencies of polymorphisms DNA from 235 patients with advanced cancers refractory to conventional therapies treated with oncolytic virotherapy were genotyped for FcgRIIa-H131R and FcgRIIIa-V158F polymorphisms by TaqMan-based qPCR
Analyses of patient survival and treatment responses according to FcgRIIa and FcgRIIIa genotypes The median overall survival (OS) time after the first treatment with oncolytic adenoviruses of the studied patients was 130 days
Summary
Oncolytic viruses have shown potential as cancer therapeutics, but not all patients seem to benefit from therapy. 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. Adenoviruses per se are known to be highly immunogenic but it seems that even stronger stimulation of patient’s own immune system is required to fully overcome the immunosuppressive tumor microenvironment and to ensure a long-lasting effect. In this regard, boosting the immunogenicity of the virus e.g. by inserting immunostimulatory transgenes has shown intriguing results [4,5]. Currently there are no biomarkers available for selecting the right patients for such therapy or vice versa
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