KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children’s Oncology Group

Abstract

BackgroundIn the Children’s Oncology Group ANBL1221 phase 2 trial for patients with first relapse/first declaration of refractory high-risk neuroblastoma, irinotecan and temozolomide (I/T) combined with either temsirolimus (TEMS) or immunotherapy (the anti-GD2 antibody dinutuximab (DIN) and granulocyte macrophage colony stimulating factory (GM-CSF)) was administered. The response rate among patients treated with I/T/DIN/GM-CSF in the initial cohort (n=17) was 53%; additional patients were enrolled to permit further evaluation of this chemoimmunotherapy regimen. Potential associations between immune-related biomarkers and clinical outcomes including response and survival were evaluated.MethodsPatients were evaluated for specific immunogenotypes that influence natural killer (NK) cell activity, including killer immunoglobulin-like receptors (KIRs) and their ligands, Fc gamma receptors, and NCR3. Total white cells and leucocyte subsets were assessed via complete blood counts, and flow cytometry of peripheral blood mononuclear cells was performed to assess the potential association between immune cell subpopulations and surface marker expression and clinical outcomes. Appropriate statistical tests of association were performed. The Bonferroni correction for multiple comparisons was performed where indicated.ResultsOf the immunogenotypes assessed, the presence or absence of certain KIR and their ligands was associated with clinical outcomes in patients treated with chemoimmunotherapy rather than I/T/TEMS. While median values of CD161, CD56, and KIR differed in responders and non-responders, statistical significance was not maintained in logistic regression models. White cell and neutrophil counts were associated with differences in survival outcomes, however, increases in risk of event in patients assigned to chemoimmunotherapy were not clinically significant.ConclusionsThese findings are consistent with those of prior studies showing that KIR/KIR-ligand genotypes are associated with clinical outcomes following anti-GD2 immunotherapy in children with neuroblastoma. The current study confirms the importance of KIR/KIR-ligand genotype in the context of I/T/DIN/GM-CSF chemoimmunotherapy administered to patients with relapsed or refractory disease in a clinical trial. These results are important because this regimen is now widely used for treatment of patients at time of first relapse/first declaration of refractory disease. Efforts to assess the role of NK cells and genes that influence their function in response to immunotherapy are ongoing.Trial registration numberNCT01767194.

Targeting the myeloid microenvironment in neuroblastoma

“…Similarly, Zeng et al found a positive correlation between higher numbers of tumor-infiltrating macrophages and neutrophils and increased OS [ 37 ]. Conversely, other studies did not observe significant associations between neutrophils and survival [ 38 ], or even found the opposite [ 39 – 41 ]. Zhang et al reported that a higher NLR was associated with reduced OS [ 39 ].…”

“…Zhang et al reported that a higher NLR was associated with reduced OS [ 39 ]. Erbe et al did not find a significant correlation between NLR and survival, but they did note that a higher neutrophils count was associated with shortened event-free survival (EFS) [ 41 ]. Lee et al observed that elevated neutrophil counts were associated with a higher cumulative incidence of disease progression, although not significantly impacting EFS or OS [ 40 ].…”

“…Monocytes and macrophages play a significant role within the myeloid compartment of the TME and possess phagocytic abilities. Unlike neutrophils, circulating monocyte levels or leukocyte-to-monocyte ratio (LMR) are not linked to overall survival [ 38 , 41 ]. Tumor-derived chemokines and cytokines can recruit monocytes to the TME, where they can differentiate into monocyte-derived macrophages [ 67 ].…”

Bispecific GD2 x B7-H3 Antibody Improves Tumor Targeting and Reduces Toxicity while Maintaining Efficacy for Neuroblastoma

“…Genotyping for FCߛR3A, FCߛR2A and FCߛR2C and categorical determinations for highaffinity FCߛRs vs low-affinity FCߛRs were performed as previously described. 66,67,68 Antibody Internalization Assays Antibodies were labeled with pHrodo TM iFL Red (ThermoFisher) per the manufacturer's protocol. Antibodies were plated together with neuroblastoma cell lines and imaged every 3-6 hours for 48 hours via an Incucyte S3 live cell imaging platform.…”

Children's Oncology Group's 2023 blueprint for research: Neuroblastoma

“…Studies of the tumor microenvironment (including immune infiltrates) and serum immunocorrelative studies have been undertaken to examine prognostic implications and to predict response to anti-GD2 immunotherapy regimens. [37][38][39][40] With the exception of host polymorphisms of KIR/KIR-ligand genes, 39,41 no other predictive biomarkers have been identified. However, additional correlative studies, including monitoring GD2 expression, are ongoing using samples from COG trials.…”