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

Abstract

PURPOSE In 2010, a Children’s Oncology Group (COG) phase III randomized trial for high-risk neuroblastoma patients (ANBL0032) demonstrated improved event-free survival (EFS) and overall survival (OS) following treatment with an immunotherapy regimen of dinutuximab, GM-CSF, IL-2, and isotretinoin compared to treatment with isotretinoin alone. Dinutuximab, a chimeric anti-GD2 monoclonal antibody, acts in part via NK cells. Killer Immunoglobulin-like Receptors (KIRs) 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. PATIENTS AND METHODS 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. In contrast, for patients with the complementary KIR/KIR-ligand genotypes, clinical outcome was not significantly different for patients that received immunotherapy vs. 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, while 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 utilized prospectively for identifying patients likely to benefit from certain cancer immunotherapy regimens.

Exploiting the internalization feature of an antibody against the glycosphingolipid SSEA‐4 to deliver immunotoxins in breast cancer cells

“…Moxetumomab pasudotox is a recombinant immunotoxin targeting CD22, composed of an immunoglobulin light‐chain variable domain and a heavy‐chain variable domain genetically fused to a truncated form of Pseudomonas exotoxin A . Moreover, antiglycolipid‐targeted therapy is showing great promise in the treatment of neuroblastoma; Dinutuximab, an antibody against ganglioside GD2, was approved in 2015 by the Food and Drug Administration and has been used as a second‐line treatment for children with high‐risk neuroblastoma . In addition, it was shown that the antitumor efficacy of Rituximab, a monoclonal antibody against CD20 currently approved for the treatment of recurrent/refractory follicular B‐cell non‐Hodgkin's lymphomas, can be strongly augmented by its conjugation to saporin .…”

“…39 Moreover, antiglycolipid-targeted therapy is showing great promise in the treatment of neuroblastoma; Dinutuximab, an antibody against ganglioside GD2, was approved in 2015 by the Food and Drug Administration and has been used as a second-line treatment for children with high-risk neuroblastoma. 40,41 In addition, it was shown that the antitumor efficacy of Rituximab, a monoclonal antibody against CD20 currently approved for the treatment of recurrent/refractory follicular B-cell non-Hodgkin's lymphomas, can be strongly augmented by its conjugation to saporin. 42 Interestingly, immunotoxin toxicity can be improved by coadministration with the chemotherapeutic drug fludarabine in lymphoma cell lines.…”

Long-term disease stabilization in a patient with relapsed neuroblastoma after allogeneic hematopoietic stem cell transplantation. Clinical case and literature review

“…Учитывая способность NK-клеток к лизису клеток НБ [15] и их потенциальную активность в контексте алло-ТГСК [16], обсуждается эффективность иммуноадоптивной терапии с использованием NK-клеток. О роли KIR-рецепторов и их лигандов в иммунном ответе косвенно свидетельствует ассоциация их генотипа с исходом терапии у реципиентов ауто-ТГСК [17] К л и н и ч е с к и е н а б л ю д е н и я ших иммунотерапию [18]. Дополнительным аргументом в пользу применения KIR-несовместимых NK-клеток именно в контексте алло-ТГСК может послужить их способность индуцировать экспрессию HLA I класса [19], что делает клетки опухоли потенциально более чувствительными к воздействию антигенспецифичных Т-лимфоцитов.…”

Data analysis to modeling to building theory in NK cell biology and beyond: How can computational modeling contribute?

“…High‐dimensional datasets such as RNA‐seq data describing changes in NK cell gene expressions NKR gene sequences, and protein expressions in single NK cells (e.g., CyTOF) provide detailed description regarding the involvement of NK cell populations in immune responses elicited by a viral infection or by an organ transplant. Data‐driven models are being increasingly applied to develop predictive computational frameworks to determine precision biomarkers in patients for optimizing NK cell and T cell responses in immunotherapies or organ transplants. However, a key challenge in this endeavor is to know what measured variables should be included in such computational models.…”