CALGB 150905 (Alliance): Rituximab Broadens the Antilymphoma Response by Activating Unlicensed NK Cells

Abstract

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 hypo-responsive 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 follicular lymphoma patients treated with rituximab-containing mAb combinations and show that rituximab triggers responses from all NK cell populations regardless of licensing. Neither IL-2 nor accessory cells are required for activating unlicensed NK cells, but both can augment rituximab-mediated ADCC. Moreover, in 101 follicular lymphoma patients treated with rituximab-containing mAb combinations, a “missing ligand” genotype (predictive of unlicensed NK cells) is associated with higher 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 hypo-responsive, 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.

Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD2 antibody ch14.18/CHO show higher ADCC levels and improved event-free survival

“…[17][18][19] These observations were also made in lymphoma patients treated with rituximab suggesting KIR/ KIRL-dependent effects in NK-mediated tumor cell lysis. 20 Surprisingly, in the present study we did not find significant differences in ADCC and EFS between matched and mismatched inhibitory KIR/KIRL genotypes in our patient cohort (data not shown), indicating only a minor role for exclusive consideration of the 2DL3/HLA-C1 and 3DL1/HLA-Bw4 KIR/KIRL repertoire. Interestingly, analysis of patients with combined unfavorable genotypes revealed significantly decreased EFS rates in 2DS2-negative missing patients with the inhibitory 3DL1/HLA-Bw4 match, again emphasizing the important contribution of 2DS2 to the efficacy of immunotherapy with ch14.18/CHO.…”

“…[17][18][19] Similar observations were made in lymphoma patients treated with rituximab. 20 Extending on these results, interactions of activating KIR/KIRL has been recently studied in a number of malignancies. 8 Underlying the diversity of KIR genomic regions, there are patterns that are conserved within the population suggesting conservation of distinct haplotypes that can be separated into two main groups described as haplotypes A and B.…”

NK Cell Activation in the Antitumor Response Induced by IFN-α Dendritic Cells Loaded with Apoptotic Cells from Follicular Lymphoma Patients

“…To the best of our knowledge, such a direct killing was not documented previously, likely because CD56 + NK cells are rarely detected in FL microenvironment, and MHC class I expression by FL cells typically acts as a negative control for NK cell activation. Of note, FL cell killing by NK cells generally was shown to rely on Ab-dependent cellular cytotoxicity activity in the presence of anti-CD20 Ab (23,24). Conversely, we showed that IFN-DC quickly formed conjugates with NK cells and that two independent mechanisms were synergistically operating in NK cell activation by IFN-DC: expression of MICA/B receptors on IFN-DC and their interaction with the cognate receptor NKG2D on NK cells, as well as trans-presentation of membrane-bound IL-15 by IFN-DC to NK cells.…”

Mutation load and an effector T-cell gene signature may distinguish immunologically distinct and clinically relevant lymphoma subsets

“…[10][11][12][13][14][15] In the prerituximab era, a mixed T-cell gene signature was associated with improved outcomes, whereas an expression signature enriched for monocyte genes was associated with poor prognosis. 10 Recent studies suggest, however, that the therapeutic setting may impact these associations, with macrophage infiltration correlating with worse outcomes after rituximab, cyclophosphamide, vincristine, and prednisone, but improved outcomes among patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.…”