Associations of Fc gamma receptor (FcgR2a, FcgR3a and FcgR2c) genotype with outcome in metastatic renal cell carcinoma (mRCC) patients receiving high dose interleukin 2 (HD-IL2)

• Published in: Journal for immunotherapy of cancer 2015-11, Vol.3 (Suppl 2), p.P300-P300, Article P300
• Main Authors: Erbe, Amy K, Wang, Wei, Kim, Kyung Mann, Carmichael, Laskeesha, Gallendberger, MIkayla, Hess, Dustin, Mendonca, Eneida A, Song, Yiqiang, Hank, Jacquelyn A, Chen, Su-Chun, Signoretti, Sabina, Atkins, Michael B, Carlson, Alexander, Mier, James, Panka, David, McDermott, David F, Sondel, Paul M
• Format: Article
• Language: English
• Subjects: Antibodies; Antigens; Carcinoma, Renal cell; Care and treatment; Development and progression; Drug metabolism; Genetic aspects; Genotype; Health aspects; Immunotherapy; Interleukin-2; Kidney cancer; Patient outcomes; Patients; Poster Presentation
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1186/2051-1426-3-S2-P300

HD-IL2 was given to patients with mRCC in a prospective trial (ClinicalTrials.gov ID: NCT00554515) that demonstrated an overall response rate of 25%. To identify predictors of response, we genotyped patients for single nucleotide polymorphisms (SNPs) in FcgR genes: FcgR2a, FcgR3a, and FcgR2c. These FcgRs are variably expressed on immune cells, and bind to the IgG portion of antibodies, triggering activation.FcgR2a [SNP = histidine/arginine (H/R); expressed on neutrophils, monocytes-macrophages and antigen-presenting cells (APCs)] and FcgR3a [SNP = valine/phenylalanine (V/F); expressed on NK cells and some APCs] impact patient response to immunotherapy [mainly monoclonal antibody-based (mAb) therapies] in several malignancies, as both FcgR2a-H and FcgR3a-V have higher antibody binding affinity than FcgR2a-R or FcgR3a-F, respectively. FcgR2c, also expressed on NK cells, has a SNP that regulates its expression [C nucleotide = expression; T nucleotide = non-expression (C/T)]. About 20-40% of individuals express FcgR2c; little is known about the role of FcgR2c expression in cytokine-based immunotherapy.We found associations of FcgR genotypes with patient response to HD-IL2. Dual combination analyses of FcgR3a with FcgR2a genotypes revealed significantly improved %Tumor Shrinkage in patients with either FcgR3a-VV and/or FcgR2a-HH (n=34) as compared to those patients genotyped as FcgR3a-VF or FF with FcgR2a-HR or RR (n=70) (p=0.047). For analyses including both FcgR3a and FcgR2c genotypes, significantly improved OS was seen in those with ≥2 alleles of either FcgR3a-V and/or FcgR2c-C (n=27) vs. those with < 2 alleles of either FcgR3a-V and/or FcgR2c-C (n=79) (p=0.013). We further considered combinations that included the genotypes of all 3 genes; we identified 42 patients with “favorable” genotypes and 64 with “unfavorable”. We saw significant improvement in the %Tumor shrinkage (p = 0.033) and a trend for improvement in OS (p = 0.071) in the “favorable genotype” group.As reported previously by others, some cancer patients make endogenous anti-tumor Ab. The association of these “favorable” FcgR genotypes with outcome suggests there may be a beneficial interaction of “favorable” FcR genotypes with endogenous anti-tumor Ab. Favorable FcgRs may support the induction of in vivo antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP). In addition, ADCP by APC with a favorable pattern of FcgRs, may be playing a role in enh