humanised dinutuximab (Hu14.18K322A) / St. Jude Children's Research Hospital, Essential Pharma - LARVOL DELTA

KAT6A and B inhibition increases efficacy of differentiation and GD2 targeting immunotherapy in neuroblastoma (AACR 2025) - "Reflecting the epigenetic reprogramming of these tumor cells, we observed that expression of GD2, a cell surface glycosphingolipid that is a target of antibody-based and CAR T cell therapies in neuroblastoma, was induced on GD2low neuroblastoma cells by treatment with retinoic acid plus PF-9363 both in vitro and in vivo, leading to increased effectiveness of anti-GD2 CAR T cell therapy in neuroblastoma. These studies nominate KAT6A/B inhibition as a novel approach to enhance the effectiveness of differentiation and GD2-immunotherapy in neuroblastoma and may be relevant for other tumors of neuro-ectodermal origin."

Clinical • IO biomarker • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • GATA3 • HOXB6 • KAT6A • MYCN • PHOX2B

Therapy for Children With Advanced Stage Neuroblastoma (clinicaltrials.gov) - P2 | N=153 | Active, not recruiting | Sponsor: St. Jude Children's Research Hospital | Trial completion date: Dec 2024 ➔ Dec 2025

Trial completion date • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • MYCN

Survival Outcomes in Children with High-Risk Neuroblastoma Treated with Anti-GD2 Immunotherapy: A Single-Arm Systematic Review and Meta-Analysis (AAP-NCE 2024) - "Of these, 11 studies evaluated Dinutuximab, three studies evaluated Naxitamab, two studies hu14.18K322A, and two studies 3F8. This single-arm meta-analysis suggests that high-risk Neuroblastoma patients may benefit from anti-GD2 immunotherapy, with promising impacts on OS, PFS, and EFS."

Retrospective data • Review • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

Survival rates in high-risk neuroblastoma patients undergoing anti-GD2 immunotherapy: A single arm meta-analysis and systemic review (ESMO 2024) - "Among these, five studies assessed Dinutuximab; six assessed Dinutuximab beta; four investigated Naxitamab; two examined hu14.18K322A, and two evaluated 3F8. This single-arm meta-analysis suggests that high-risk Neuroblastoma patients may benefit from anti-GD2 immunotherapy, with promising impacts on OS, PFS, and EFS."

Retrospective data • Review • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • IL2

Hu14.18K.322A Causes Direct Cell Cytotoxicity and Synergizes with Induction Chemotherapy in High-Risk Neuroblastoma. (PubMed, Cancers (Basel)) - "In this study, we examined the direct cytotoxic effects of the humanized anti-GD2 antibody hu14.18K322A (hu14) on NB cell lines, by exploring the associated cell-death pathways...Our comprehensive investigation provides valuable insights into the multifaceted effects of hu14 on NB cells, shedding light on its direct cytotoxicity, cell-death pathways, and interactions with induction chemotherapy drugs. This study contributes to the evolving understanding of anti-GD2 antibody therapy and its potential synergies with conventional treatments in the context of NB."

Journal • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

A pilot study of post-consolidation chemoimmunotherapy for high-risk neuroblastoma (ANBL19P1): A report from the Children's Oncology Group. (ASCO 2024) - P2 | "Therapy, administered every 28 days, consisted of temozolomide and irinotecan on Days 1-5, dinutuximab on Days 2-5, and sargramostim on Days 6-12 during Cycles 1-5; isotretinoin on Days 8-21 during Cycles 1-6... Administration of post-consolidation chemoimmunotherapy in pts who underwent tandem ASCT is tolerable and met pre-defined feasibility criteria. The impact of this approach on survival outcomes will be studied in a future COG trial."

Clinical • Bone Marrow Transplantation • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • Transplantation

Essential Pharma reaches agreement with AGC Biologics for late phase clinical manufacturing of its immunotherapy candidate for the treatment of high-risk neuroblastoma (GlobeNewswire) - "Essential Pharma...announced its rare disease business has signed a strategic agreement with AGC Biologics. As a leading global biopharmaceutical contract development and manufacturing organisation (CDMO), AGC Biologics will produce Hu1418K322A (Hu14.18), a humanised monoclonal antibody being developed for Essential Pharma for the treatment of high-risk neuroblastoma (HRNB). Under the agreement, AGC Biologics will support the process development, scale-up and manufacturing as Essential Pharma plans to commence clinical activities and ongoing regulatory agency interactions over the coming months."

Licensing / partnership • Neuroblastoma

Orphan Designation: Treatment of Neuroblastoma (FDA) - Date Designated: 04/08/2024

Orphan drug • Neuroblastoma

Direct cytotoxicity of hu14.18K.322A in high-risk neuroblastoma (AACR 2024) - "Taken together, our findings suggest that hu14.18K322A induces direct cell cytotoxicity in a subset of high-risk Neuroblastoma and synergizes well with standard chemotherapy drugs. Furthermore, our research highlights the complex nature of signaling pathways involved in hu14-mediated cytotoxicity that can be harnessed towards targeted therapy."

CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

Essential Pharma acquires Renaissance Pharma Ltd with its clinical stage immunotherapy for the treatment of high-risk neuroblastoma (GlobeNewswire) - "Essential Pharma...announces that it has completed the acquisition of the entire issued share capital of Renaissance Pharma Ltd. Renaissance Pharma is a clinical stage pharmaceutical company focused on the development of life changing therapies in paediatric rare disease, with its lead asset being Hu14.18K322A (Hu14.18) - an immunotherapy currently in Phase II clinical development for the treatment of high-risk neuroblastoma (HRNB)....Essential Pharma will be responsible for clinical development and defining the optimal route for regulatory approval and eventual commercial launch of Hu14.18."

M&A • Neuroblastoma

Therapy for Children With Advanced Stage Neuroblastoma (clinicaltrials.gov) - P2 | N=153 | Active, not recruiting | Sponsor: St. Jude Children's Research Hospital | Trial completion date: Dec 2023 ➔ Dec 2024

Metastases • Trial completion date • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • MYCN

Renaissance Pharma launches today and announces the in-licensing of Hu14.18K322A (Hu14.18) from St. Jude Children’s Research Hospital for the treatment of High-Risk Neuroblastoma (GlobeNewswire) - "Renaissance Pharma Ltd...today launches and announces the signing of an exclusive license agreement with St. Jude Children’s Research Hospital ('St. Jude') for Hu14.18, a humanised antibody in development by St. Jude for the treatment of newly diagnosed high-risk neuroblastoma....Under the terms of the licensing agreement, Renaissance Pharma has secured exclusive development, manufacturing and commercialisation rights to US, Canada, Europe, China, Japan and Turkey."

Licensing / partnership • Neuroblastoma • Oncology • Solid Tumor

A multicenter cooperative group study of late effects after high-risk neuroblastoma: COG ALTE15N2—LEAHRN study. (ASCO 2023) - "ASCT conditioning included: Busulfan/Melphalan (BuMel) (18%), Carboplatin/Etoposide/Melphalan (CEM) (73%), Thiotepa/Cytoxan (19%), and total body irradiation (5%)...Use of carboplatin during ASCT was not assocoiated with increased ototoxicity risk for any category of cisplatin induction dose... The burden of late toxicity in HRNBL survivors is substantial. Anti-GD2 immunotherapy and isotretinoin do not appear to be associated with SMN, ototoxicity, growth failure, or RLD."

Clinical • Acute Myelogenous Leukemia • Cardiovascular • CNS Tumor • Congestive Heart Failure • Endocrine Disorders • Heart Failure • Hypertension • Infectious Disease • Neuroblastoma • Neuroendocrine Tumor • Oncology • Otorhinolaryngology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Sarcoma • Solid Tumor • Transplantation

TREATMENT OF HIGH-RISK NEUROBLASTOMA USING DINUTUXIMAB CHEMOIMMUNOTHERAPY IN ALL CYCLES OF INDUCTION (ASPHO 2023) - P2 | "Background: The addition of an anti-GD2 monoclonal antibody (hu14.18K322A) to 6 cycles of Induction chemotherapy for the treatment of patients with high-risk neuroblastoma (HRNBL) led to an end of Induction (EOI) objective response rate (ORR; > partial response [PR]) of 93.8% in a single institution phase 2 clinical trial (NB2012, NCT01857934). The administration of DIN and GM-CSF to COG Induction for patients with HRNBL had an encouraging EOI ORR. A randomized phase 3 study of Induction chemoimmunotherapy is warranted."

CNS Tumor • Neuroblastoma • Neuroendocrine Tumor • Oncology • Solid Tumor • CSF2 • IL2

KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children's Oncology Group. (PubMed, J Immunother Cancer) - P2 | "These 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."

Clinical data • IO biomarker • Journal • CNS Tumor • Neuroblastoma • Neuroendocrine Tumor • Oncology • Pediatrics • Solid Tumor • CSF2 • KLRB1 • NCAM1

Early response rates and Curie scores at end of induction: An update from a phase II study of an anti-GD2 monoclonal antibody (mAb) with chemotherapy (CT) in newly diagnosed patients (pts) with high-risk (HR) neuroblastoma (NB). (ASCO 2017) - P2; "Our primary objective is to compare the response rate (RR; defined as ≥ PR) after two courses of CT with cyclophosphamide (CTX)/topotecan (TPT) and hu14.18K322A with GM-CSF and IL-2 to the RR reported by Park et al. The addition of hu14.18K322A to two courses of CTX/TPT significantly improves the RR compared to two courses of CTX/TPT alone (32/42 vs 12/30 as reported by Park et al,; P = 0.000004). The improved median CS of the stage 4 patients from 18 at diagnosis to 0 at EoI suggest the improvement in early RR may translate into improved EFS as well."

Biomarker • Clinical • P2 data • Biosimilar • Neuroendocrine Tumor • Oncology

Mesenchymal and adrenergic cell lineage states in neuroblastoma possess distinct immunogenic phenotypes. (PubMed, Nat Cancer) - "Mesenchymal lineage cells promote T cell infiltration by secreting inflammatory cytokines, are efficiently targeted by cytotoxic T and natural killer cells and respond to immune checkpoint blockade. Together, we demonstrate that distinct immunogenic phenotypes define the divergent lineage states of neuroblastoma and highlight the immunogenic potential of the mesenchymal lineage."

IO biomarker • Journal • Preclinical • Immune Modulation • Inflammation • Neuroblastoma • Oncology • Solid Tumor

Global Neuroblastoma Network: An international multidisciplinary neuroblastoma tumor board for resource-limited countries. (PubMed, Pediatr Blood Cancer) - "This report shows the utility of an international tumor board for LMIC focused on a challenging solid tumor where local expertise may be limited, with international multidisciplinary expert participation and educational sessions."

Journal • Bone Marrow Transplantation • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • Transplantation • MYCN

"This improved, genetically modified version of Unituxan (dinutuximab), an approved monoclonal antibody (mAb) targeting the disialoganglioside GD2. It has a significantly better tolerance profile and is known as hu14.18K322A, which improved survival rates and outcomes." (@TechnologyAvai1)

Improved Outcome in Children With Newly Diagnosed High-Risk Neuroblastoma Treated With Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A. (PubMed, J Clin Oncol) - "Adding hu14.18K322A to induction chemotherapy improved early objective responses, significantly reduced tumor volumes in most patients, improved end-of-induction response rates, and yielded an encouraging 3-year EFS. These results, if validated in a larger study, may be practice changing."

Clinical • Journal • P2 data • Neuroblastoma • Oncology • Solid Tumor • CSF2

Therapy for Children With Advanced Stage Neuroblastoma (clinicaltrials.gov) - P2; N=153; Active, not recruiting; Sponsor: St. Jude Children's Research Hospital; Trial completion date: Jul 2021 ➔ Dec 2023; Trial primary completion date: Jan 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Neuroblastoma • Oncology • Solid Tumor • CSF2 • IL2 • MYCN

Combination Chemotherapy, Monoclonal Antibody, and Natural Killer Cells in Treating Young Patients With Recurrent or Refractory Neuroblastoma (clinicaltrials.gov) - P1; N=34; Active, not recruiting; Sponsor: St. Jude Children's Research Hospital; Trial completion date: Feb 2019 ➔ Oct 2018

Trial completion date • Biosimilar • Hematological Malignancies • Neuroendocrine Tumor • Oncology • Solid Tumor

Pretreatment Anti-Therapeutic Antibodies (PATA) in Patients Treated With hu14.18K322A Antibody (clinicaltrials.gov) - P=N/A; N=76; Completed; Sponsor: St. Jude Children's Research Hospital; Active, not recruiting ➔ Completed; Trial completion date: Oct 2020 ➔ Apr 2020

Clinical • Trial completion • Trial completion date • Melanoma • Neuroblastoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

A Pilot Study of Immunotherapy Including Haploidentical NK Cell Infusion Following CD133+ Positively-Selected Autologous Hematopoietic Stem Cells in Children With High Risk Solid Tumors or Lymphomas (clinicaltrials.gov) - P1; N=8; Completed; Sponsor: St. Jude Children's Research Hospital; Recruiting ➔ Completed; N=36 ➔ 8; Trial primary completion date: Sep 2020 ➔ Dec 2017

Clinical • Enrollment change • Trial completion • Trial primary completion date • Biosimilar • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Neuroendocrine Tumor • Non-Hodgkin’s Lymphoma • Oncology

A Phase II Trial of Hu14.18K322A in Combination with Induction Chemotherapy in Children with Newly Diagnosed High-Risk Neuroblastoma. (PubMed, Clin Cancer Res) - "Adding hu14.18K322A to induction chemotherapy produced early PR or better in most patients, reduced tumor volumes, improved CSs at the end of induction, and yielded an encouraging 2-year EFS. These results, if validated in a larger study, may change the standard of care for children with high-risk neuroblastoma."

Clinical • Combination therapy • Journal • P2 data • Neuroblastoma • Oncology • Solid Tumor