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Front Immunol. 2017 Jun 12;8:675. doi: 10.3389/fimmu.2017.00675. eCollection 2017.

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.

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Department of Human Oncology, University of Wisconsin, Madison, WI, United States.
Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, United States.
Dana-Farber Cancer Institute/Boston Children's Cancer and Blood Disorder Center, Harvard Medical School, Boston, MA, United States.
COG Statistics and Data Center, Department of Biostatistics, University of Florida, Gainesville, FL, United States.
Department of Biostatistics, Harvard University, Dana Farber Cancer Institute, Boston, MA, United States.
Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, United States.
Provenance Biopharmaceuticals, Carlisle, MA, United States.
Seattle Children's Hospital/University, Seattle, WA, United States.
University of Washington, Seattle, WA, United States.
New York Medical College, Valhalla, NY, United States.
Department of Medicine, University of Minnesota, Minneapolis, MN, United States.
Levine Children's Hospital, Charlotte, NC, United States.
Department of Medicine, Washington University, St. Louis, MO, United States.
Department of Pediatrics, Hematology/Oncology, Moores Cancer Center, University of California San Diego, San Diego, CA, United States.
Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Department of Pediatrics, University of Wisconsin-Madison, Madison, WI, United States.


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.


HLA; HLA-Bw4; KIR; KIR-ligand; MHC class I; cancer immunotherapy; natural killer cells

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