Cancer Gene Therapy Group, Department of Pathology and Transplantation laboratory, Haartman Institute, University of Helsinki, Haartmaninkatu 3, Helsinki 00290, Finland.
J Transl Med. 2013 Aug 21;11:193. doi: 10.1186/1479-5876-11-193.
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.
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.
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).
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.
溶瘤病毒已显示出作为癌症治疗剂的潜力，但并非所有患者似乎都从治疗中受益。Fc 受体（FcgR）多态性导致 IgG 与受体同种型之间的结合亲和力改变，因此有助于免疫防御机制的差异。已经确定 FcgR 多态性与对不同免疫疗法的反应性之间存在关联。鉴于越来越多的人认为免疫因素可能决定溶瘤病毒治疗的疗效，我们研究了 FcgR 多态性在溶瘤腺病毒治疗的背景下是否具有预后和/或预测意义。
使用 TaqMan 基于 qPCR 对 235 名晚期实体瘤患者的两种 FcgR 多态性 FcgRIIa-H131R（rs1801274）和 FcgRIIIa-V158F（rs396991）进行基因分型。将基因型与患者生存和肿瘤成像数据相关联。
在接受溶瘤腺病毒治疗的患者中，如果患者具有 FcgRIIIa-VV/FcgRIIa-HR（VVHR）基因型组合，总生存期明显缩短（P=0.032）。相比之下，如果 FFHR 和 FFRR 基因型的患者接受 GM-CSF 武装的腺病毒治疗，与其他病毒相比，总生存期明显延长（P=0.004 和 P=0.006）。用无武装病毒治疗这些患者与较短的生存相关（P<0.0005 和 P=0.016）。用 CD40L 武装的病毒治疗 FFHH 个体的生存期长于用其他病毒治疗的生存期（P=0.047）。
我们的数据与以下假设一致，即 FcgR 多态性引起的效应细胞功能的个体差异，如 NK 细胞介导的抗体依赖性细胞毒性（ADCC）和 APC 对肿瘤抗原的呈递，可能在溶瘤病毒治疗的有效性中起作用。如果在更大的人群中得到证实，FcgR 多态性可能成为溶瘤腺病毒治疗的预后和预测生物标志物，以更好地选择临床试验患者。此外，基因型、不同病毒和存活之间的假定关联暗示了潜在的重要机制问题。
