CALGB 150905 (Alliance): rituximab broadens the antilymphoma response by activating unlicensed NK cells.

Journal Article (Journal Article)

Natural killer (NK) cells contribute to clinical responses in patients treated with rituximab, but the rules determining NK-cell responsiveness to mAb therapies are poorly defined. A deeper understanding of the mechanisms responsible for antibody-dependent cellular cytotoxicity (ADCC) could yield useful biomarkers for predicting clinical responses in patients. Unlicensed NK cells, defined as NK cells lacking expression of an inhibitory KIR for self-HLA class I ligands, are hyporesponsive in steady state, but are potent effectors in inflammatory conditions. We hypothesized that antitumor antibodies such as rituximab can overcome NK-cell dependence on licensing, making unlicensed NK cells important for clinical responses. Here, we examined the influences of variations in KIR and HLA class I alleles on in vitro responses to rituximab. We tested the clinical significance in a cohort of patients with follicular lymphoma treated with rituximab-containing mAb combinations, and show that rituximab triggers responses from all NK-cell populations regardless of licensing. Neither IL2 nor accessory cells are required for activating unlicensed NK cells, but both can augment rituximab-mediated ADCC. Moreover, in 101 patients with follicular lymphoma treated with rituximab-containing mAb combinations, a "missing ligand" genotype (predictive of unlicensed NK cells) is associated with a higher rate of progression-free survival. Our data suggest that the clinical efficacy of rituximab may be driven, in part, by its ability to broaden the NK-cell repertoire to include previously hyporesponsive, unlicensed NK cells. A "missing ligand" KIR and HLA class I genotype may be predictive of this benefit and useful for personalizing treatment decisions in lymphomas and other tumors.

Full Text

Duke Authors

Cited Authors

  • Du, J; Lopez-Verges, S; Pitcher, BN; Johnson, J; Jung, S-H; Zhou, L; Hsu, K; Czuczman, MS; Cheson, B; Kaplan, L; Lanier, LL; Venstrom, JM

Published Date

  • September 2014

Published In

Volume / Issue

  • 2 / 9

Start / End Page

  • 878 - 889

PubMed ID

  • 24958280

Pubmed Central ID

  • PMC4264658

Electronic International Standard Serial Number (EISSN)

  • 2326-6074

Digital Object Identifier (DOI)

  • 10.1158/2326-6066.CIR-13-0158


  • eng

Conference Location

  • United States