HLA-Bw4-I-80 Isoform Differentially Influences Clinical Outcome As Compared to HLA-Bw4-T-80 and HLA-A-Bw4 Isoforms in Rituximab or Dinutuximab-Based Cancer Immunotherapy

Amy K Erbe,Patrick K Reville,Jacquelyn A Hank,Lakeesha Carmichael,Fangxin Hong,Paul M Sondel,Julie R Park,Wei Wang,Jeffrey S Miller,Wendy B London,Arlene Naranjo,Alice L Yu,Andrew L Gilman,John M Maris,Michael D Hogarty,Younghwan Song ,Brad S Kahl ,Eneida A Mendonça ,Kyung Mann Kim ,M Fevzi Özkaynak

doi:10.3389/fimmu.2017.00675

Abstract

Killer-cell immunoglobulin-like receptors (KIRs) are a family of glycoproteins expressed primarily on natural killer cells that can regulate their function. Inhibitory KIRs recognize MHC class I molecules (KIR-ligands) as ligands. We have reported associations of KIRs and KIR-ligands for patients in two monoclonal antibody (mAb)-based trials: (1) A Children’s Oncology Group (COG) trial for children with high-risk neuroblastoma randomized to immunotherapy treatment with dinutuximab (anti-GD2 mAb) + GM-CSF + IL-2 + isotretinion or to treatment with isotretinoin alone and (2) An Eastern Cooperative Oncology Group (ECOG) trial for adults with low-tumor burden follicular lymphoma responding to an induction course of rituximab (anti-CD20 mAb) and randomized to treatment with maintenance rituximab or no-maintenance rituximab. In each trial, certain KIR/KIR-ligand genotypes were associated with clinical benefit for patients randomized to immunotherapy treatment (immunotherapy in COG; maintenance rituximab in ECOG) as compared to patients that did not receive the immunotherapy [isotretinoin alone (COG); no-maintenance (ECOG)]. Namely, patients with both KIR3DL1 and its HLA-Bw4 ligand (KIR3DL1+/HLA-Bw4+ genotype) had improved clinical outcomes if randomized to immunotherapy regimens, as compared to patients with the KIR3DL1+/HLA-Bw4+ genotype randomized to the non-immunotherapy regimen. Conversely, patients that did not have the KIR3DL1+/HLA-Bw4+ genotype showed no evidence of a difference in outcome if receiving the immunotherapy vs. no-immunotherapy. For each trial, HLA-Bw4 status was determined by assessing the genotypes of three separate isoforms of HLA-Bw4: (1) HLA-B-Bw4 with threonine at amino acid 80 (B-Bw4-T80); (2) HLA-B-Bw4 with isoleucine at amino acid 80 (HLA-B-Bw4-I80); and (3) HLA-A with a Bw4 epitope (HLA-A-Bw4). Here, we report on associations with clinical outcome for patients with KIR3DL1 and these separate isoforms of HLA-Bw4. Patients randomized to immunotherapy with KIR3DL1+/A-Bw4+ or with KIR3DL1+/B-Bw4-T80+ had better outcome vs. those randomized to no-immunotherapy, whereas for those with KIR3DL1+/B-Bw4-I80+ there was no evidence of a difference based on immunotherapy vs. no-immunotherapy. Additionally, we observed differences within treatment types (either within immunotherapy or no-immunotherapy) that were associated with the genotype status for the different KIR3DL1/HLA-Bw4-isoforms. These studies suggest that specific HLA-Bw4 isoforms may differentially influence response to these mAb-based immunotherapy, further confirming the involvement of KIR-bearing cells in tumor-reactive mAb-based cancer immunotherapy.

Highlights

One modality of cancer immunotherapy utilizes tumor-reactive monoclonal antibodies to elicit a tumor-targeted immune response
We describe the impact of the genotype status of B-Bw4-T80, B-Bw4-I80, and a Bw4 epitope (A-Bw4), together with the genotype status of KIR3DL1, on the clinical outcome, based on a clinical outcome parameter that measured the duration of response to the treatment regimen (EFS in Children’s Oncology Group (COG); duration of response in ECOG)
In the analysis of Killer-cell immunoglobulin-like receptors (KIRs)/KIR-ligand genotypes in each of these studies, we found similar associations with outcomes based upon the influence of

Summary

Introduction

One modality of cancer immunotherapy utilizes tumor-reactive monoclonal antibodies (mAbs) to elicit a tumor-targeted immune response. Two recently completed clinical trials, in separate disease settings, utilized tumor-reactive mAbs to successfully target and treat the tumors: [1] the combination of dinutuximab with. Natural killer (NK) cells can contribute to the response to tumorreactive mAb-based immunotherapeutics through antibodydependent cellular cytotoxicity (ADCC). The ability of NK cells to elicit ADCC is regulated by activating and inhibiting signaling. Killer-cell immunoglobulin-like receptors (KIRs) are a class of receptors expressed on NK cells that influence such signaling [3, 4]. Most inhibitory KIRs interact with HLA class I molecules as their ligands (KIR-ligand) [5]. KIR2DL1 binds to HLAC2, KIR2DL2 and KIR2DL3 bind to HLA-C1, and KIR3DL1 recognizes the Bw4 epitope of HLA-A and HLA-B [6, 7]

Methods

Results

Conclusion