Rituximab Infusion Induces NK Activation in Subjects with the High Affinity CD16 Polymorphism.
Authors: Weiner George J , Veeramani Suresh , Wang Siao-Yi , Dahle Christopher , Blackwell Sue , Jacobus Laura , Knutson Tina , Knutson Allison C , Smith Brian J , Link Brian K 
Published: October 2019

Abstract 1705

Poster Board I-731

The CD16 (FcgammaRIIIa) has a functional polymorphism at position 158. CD16 with valine at position 158 (V) has higher affinity for human IgG1 than does CD16 with phenylalanine at position 158 (F). Follicular lymphoma patients with V have a higher response rate to single agent rituximab. In vitro, NK cells from subjects with V are activated at lower rituximab concentrations than NK cells from subjects with F. Little is known about the in vivo effects of rituximab on NK activation, and the influence CD16 polymorphisms have on that activation. The current studies were designed to explore the relationship between CD16 polymorphisms and NK cell activation in patients receiving rituximab for lymphoma.

Subjects included 17 lymphoma patients with a variety of histologies scheduled to receive rituximab at the standard dose (375 mg/M2). Some had received prior treatment with rituximab, but not within the prior 6 months. Subjects did not receive recent or concurrent prednisone or immunosuppressive drugs. Blood was obtained immediately prior to initiation of the rituximab infusion, and 4 hours after the initiation of the infusion. CBC, NK cell number, NK cell CD16 and NK cell CD54 were determined at time 0 and time 4hrs, and changes in each parameter determined. All subjects were genotyped related to the CD16 position 158 polymorphism.

Genotype testing revealed 9 subjects were FF, 7 were VF, and 1 was VV. NK cell numbers for the group as a whole were lower 4 hours after initiation of therapy when compared to pre-therapy. Phenotypic changes consistent with NK cell activation at 4 hours included downmodulation of CD16 and upregulation of the adhesion molecule CD54 (ICAM-1). Subset analysis demonstrated these changes were largely limited to subjects with VF/VV. No significant change in NK cell number or activation was seen in those with FF. There was no clear correlation between infusion reactions and genotype or NK activation. Ongoing analyses include evaluation of complement, rituximab and cytokine levels.

All (n=17) p value VF/VV (n=8) p value FF (n=9) p value p value FF vs VF/VV D NK Cell # Post Rx/PreRx 0.72 +/- 0.81 0.05 0.41 +/- 0.31 0.008 1.00 +/- 1.03 0.62 0.31 D NK CD54 Post Rx/PreRx 2.14 +/- 1.69 0.0006 3.05 +/- 2.1 0.008 1.33 +/- 0.53 0.11 0.01 D NK CD16 Post Rx/PreRx 0.9 +/- 0.17 0.02 0.86 +/- 0.22 0.11 0.94 +/- 0.10 0.15 0.56

We conclude that NK activation occurs within 4 hours of infusion of rituximab. A decrease in the number of circulating NK cells occurs within 4 hours and is consistent with trafficking of NK cells out of the circulation. Subset analysis demonstrates changes in NK cell number and phenotype are statistically significant in subjects with the high affinity CD16 phenotype, but not the low affinity phenotype. This finding may help explain the enhanced efficacy of rituximab that has been observed for patients with high affinity CD16.

Disclosures

Link: Genentech: Consultancy.