KIR3DL1 and HLA-B Allele Combinations May Impact Response to Treatment in Neuroblastoma

Key Points

  • Outcomes in neuroblastoma were best in patients with noninteracting KIR3DL1 and HLA-B subtypes.
  • Strongly interacting subtypes may be a target of additional therapeutic intervention.

In a study reported in the Journal of Clinical Oncology, Forlenza et al found that noninteracting KIR3DL1 and HLA-B subtypes were associated with better response to anti-GD2 antibody treatment in neuroblastoma.

Study Details

Treatment of neuroblastoma with anti-GD2 monoclonal antibody (eg, the recently approved dinutuximab [Unituxin]) directs natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. Cytotoxicity is reduced by ligation of inhibitory killer immunoglobulin-like receptors (KIRs) by HLA class I molecules, and KIR3DL1 polymorphism affects the ability of the receptor to engage HLA-Bw4 ligands. The current study was performed to test the hypothesis that poorly interacting combinations of KIR3DL1 and HLA ligands are more permissive of monoclonal antibody–mediated antitumor effects.

In the study, KIR3DL1 and HLA-B subtyping were performed in a group of 245 patients treated with the anti-GD2 antibody 3F8 for high-risk neuroblastoma. The outcome was assessed by the degree of interaction between KIR3DL1 and HLA-B subtypes grouped as strong, weak, or noninteractors.

Best Outcome With Noninteracting Combinations

Compared with patients with strongly interacting combinations (n = 63), those with noninteracting combinations (n = 127) had the best overall survival (hazard ratio [HR] = 0.57, P = .007) and progression-free survival (HR = 0.56, P = .002). Patients with weakly interacting combinations (n = 55) had less benefit vs those with strongly interacting combinations for both overall survival (HR = 0.89, P = .627) and progression-free survival (HR = 0.85, P = .450).

On multivariate analysis, the presence of noninteracting KIR3DL1/HLA-Bw4 pairs was associated with significantly better overall survival (HR = 0.41, P ≤ .001) and progression-free survival (HR = 0.43, P ≤ .001), and the weakly interacting pairs were also associated with benefit in overall survival (HR = 0.55, P = .036) and progression-free survival (HR = 0.68, P = .153) vs strongly interacting combinations. Analysis in vitro of 3F8-mediated ADCC showed that KIR3DL1(2) and 3DS1(+) NK cells were insensitive to inhibition by neuroblastoma targets expressing HLA-Bw4.

The investigators stated: “We conclude that KIR3LD1 and HLA-B allele combinations can have a prognostic impact on patient survival after treatment with anti-GD2 monoclonal antibody that relies on NK-ADCC. The survival advantage seen in non-interacting combinations supports the therapeutic disinhibition of individuals with strongly interacting KIR and ligand pairs.”

The study was supported by the National Institutes of Health, Alex’s Lemonade Stand, and St. Baldrick’s Foundation.

Katharine C. Hsu, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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