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. 2018 Jan 1;24(1):189-196.
doi: 10.1158/1078-0432.CCR-17-1767. Epub 2017 Oct 2.

Neuroblastoma Patients' KIR and KIR-Ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report from the Children's Oncology Group (VSports app下载)

Amy K Erbe  1 , Wei Wang  1 , Lakeesha Carmichael  2 , KyungMann Kim  2 , Eneida A Mendonça  2   3 , Yiqiang Song  2 , Dustin Hess  1 , Patrick K Reville  1 , Wendy B London  4 , Arlene Naranjo  5 , Jacquelyn A Hank  1 , Mitchell B Diccianni  6 , Ralph A Reisfeld  7 , Stephen D Gillies  8 , Katherine K Matthay  9 , Susan L Cohn  10 , Michael D Hogarty  11 , John M Maris  11 , Julie R Park  12   13 , M Fevzi Ozkaynak  14 , Andrew L Gilman  15 , Alice L Yu  6   16 , Paul M Sondel  17   3
Affiliations

Neuroblastoma Patients' KIR and KIR-Ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report from the Children's Oncology Group

Amy K Erbe et al. Clin Cancer Res. .

Abstract

Purpose: In 2010, a Children's Oncology Group (COG) phase III randomized trial for patients with high-risk neuroblastoma (ANBL0032) demonstrated improved event-free survival (EFS) and overall survival (OS) following treatment with an immunotherapy regimen of dinutuximab, GM-CSF, IL2, and isotretinoin compared with treatment with isotretinoin alone. Dinutuximab, a chimeric anti-GD2 monoclonal antibody, acts in part via natural killer (NK) cells. Killer immunoglobulin-like receptors (KIR) on NK cells and their interactions with KIR-ligands can influence NK cell function. We investigated whether KIR/KIR-ligand genotypes were associated with EFS or OS in this trial. Experimental Design: We genotyped patients from COG study ANBL0032 and evaluated the effect of KIR/KIR-ligand genotypes on clinical outcomes. Cox regression models and log-rank tests were used to evaluate associations of EFS and OS with KIR/KIR-ligand genotypes. Results: In this trial, patients with the "all KIR-ligands present" genotype as well as patients with inhibitory KIR2DL2 with its ligand (HLA-C1) together with inhibitory KIR3DL1 with its ligand (HLA-Bw4) were associated with improved outcome if they received immunotherapy VSports手机版. In contrast, for patients with the complementary KIR/KIR-ligand genotypes, clinical outcome was not significantly different for patients who received immunotherapy versus those receiving isotretinoin alone. Conclusions: These data show that administration of immunotherapy is associated with improved outcome for neuroblastoma patients with certain KIR/KIR-ligand genotypes, although this was not seen for patients with other KIR/KIR-ligand genotypes. Further investigation of KIR/KIR-ligand genotypes may clarify their role in cancer immunotherapy and may enable KIR/KIR-ligand genotyping to be used prospectively for identifying patients likely to benefit from certain cancer immunotherapy regimens. Clin Cancer Res; 24(1); 189-96. ©2017 AACRSee related commentary by Cheung and Hsu, p. 3. .

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Conflict of Interest Statement:

Dr. Steve Gillies discloses equity ownership in Provenance Biopharmaceuticals of Carlisle, MA and ownership of intellectual property related to certain anti-GD2 related mAb-based agents. All other authors declare no competing financial interests V体育ios版.

Figures

Figure 1
Figure 1. Associations of overall KIR/KIR-ligand status with clinical outcome
Figure 1A – EFS; Figure 1B – OS. For immunotherapy patients, those with KIR-ligands present (Line 1: solid-black line) were compared to those with KIR-ligand missing (Line 2: dashed-black line). For isotretinoin patients, those with KIR-ligands present (Line 3: solid-red line) were compared with those with KIR-ligand missing (Line 4: dashed-red line). In addition, comparisons by treatment group were performed. For both EFS and OS, the assumption of proportional hazards was upheld, and p-values are reported from Cox regression analyses. (“*” indicates p<0.05)
Figure 2
Figure 2. Associations of KIR2DL2+/C1+ status and KIR3DL1+/Bw4+ status with clinical outcome
Figure 2A – EFS; Figure 2B – OS: For immunotherapy patients, KIR2DL2+/C1+ (Line 1: solid-black line) were compared to not KIR2DL2+/C1+ (Line 2: dashed-black line). For isotretinoin patients, KIR2DL2+/C1+ (Line 3: solid-red line) were compared with those not KIR2DL2+/C1+ (Line 4: dashed-red line). In addition, comparisons by treatment group were performed. Figure 2C – EFS; Figure 2D – OS: For immunotherapy patients, those KIR3DL1+/Bw4+ (Line 1: solid-black line) were compared to those not KIR3DL1+/Bw4+ (Line 2: dashed-black line). For isotretinoin patients, KIR3DL1+/Bw4+ (Line 3: solid-red line) were compared with those not KIR3DL1+/Bw4+ (Line 4: dashed-red line). For KIR2DL2+/C1+ status, for both EFS and OS, the proportional hazards assumption was violated, so p-values are reported from the Cox model after adjustment by incorporating time-dependent covariates. For KIR3DL1+/Bw4+ status, both EFS and OS, the proportional hazards assumption was upheld, and p-values are reported from Cox regression analyses. (“*” indicates p<0.05; “**” indicates p<0.01)
Figure 3
Figure 3. Associations of KIR2DL2+/C1+/KIR3DL1+/Bw4+ with clinical outcome
Figure 3A – EFS; Figure 3B – OS. For immunotherapy patients, KIR2DL2+/C1+/KIR3DL1+/Bw4+ (solid-black line) were compared to those not KIR2DL2+/C1+/KIR3DL1+/Bw4+ (dashed-black line). For isotretinoin patients, KIR2DL2+/C1+/KIR3DL1+/Bw4+ (solid-red line) were compared with those not KIR2DL2+/C1+/KIR3DL1+/Bw4+ (dashed-red line). In addition, comparisons by treatment group were performed. For both EFS and OS, the proportional hazards assumption was violated, so p-values are reported from the Cox model after adjustment by incorporating time-dependent covariates. (“*” indicates p<0.05; “**” indicates p<0.01).
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References

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