Targeting GD2 after allogeneic SCT: effector cell composition defines the optimal use of ch14.18 and the bispecific antibody construct NG-CU (GD2-CD3).

Autor: Arendt AM; Department of General Pediatrics, Oncology/Hematology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany. anne-marie.arendt@med.uni-tuebingen.de., Heubach F; Department of General Pediatrics, Oncology/Hematology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany., Maier CP; Department of General Pediatrics, Oncology/Hematology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany.; Department of Hematology/Oncology, Center for Internal Medicine, University Hospital, Tübingen, Germany., Giardino S; Hematopoietic Stem Cell Transplantation Unit, Department of Hematology and Oncology, IRCCS Istituto Giannina Gaslini, Genoa, Italy., Jung G; Interfaculty Institute for Cell Biology, Department of Immunology, Eberhard Karls University Tuebingen, Tübingen, Germany., Kowalewski E; Department of General Pediatrics, Oncology/Hematology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany., Rabsteyn A; Department of General Pediatrics, Oncology/Hematology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany., Amorelli G; Department of General Pediatrics, Oncology/Hematology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany., Seitz C; Department of General Pediatrics, Oncology/Hematology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany., Schlegel P; Department of General Pediatrics, Oncology/Hematology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany., Handgretinger R; Department of General Pediatrics, Oncology/Hematology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany., Lang P; Department of General Pediatrics, Oncology/Hematology, Children's University Hospital Tuebingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2023 Nov; Vol. 72 (11), pp. 3813-3824. Date of Electronic Publication: 2023 Sep 24.
DOI: 10.1007/s00262-023-03536-x
Abstrakt: We investigated whether T cell-recruiting bispecific anti-CD3/GD2 antibody NG-CU might be an alternative to therapeutic anti-GD2 monoclonal antibody (mAb) ch14.18, mediating complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) through natural killer (NK) cells for immunotherapy in high-risk/relapsed neuroblastoma after autologous/allogeneic stem cell transplantation (auto/alloSCT). Different antibody concentrations and effector-to-target ratios (E:T) were evaluated using xCELLigence RTCA system, peripheral blood mononuclear cells (PBMCs) (healthy donors and patients after alloSCT), and neuroblastoma cell lines (LS/LAN-1). Mean specific lysis of LS cells utilizing PBMCs from healthy donors and ch14.18 (1 µg/ml) was 40/66/75% after 12/24/48 h compared to 66/93/100% in the presence of NG-CU (100 ng/ml). NG-CU showed enhanced cytotoxicity compared to ch14.18, even at lower concentrations and E:T ratios, and completely eradicated LS cells after 72 h. To decipher the influence of effector cell subsets on lysis, different ratios of T and NK cells were tested. At a ratio of 1:1, ch14.18 was more effective than NG-CU. Using patient PBMCs taken at different time points posttransplant, significant lysis with both constructs was detectable depending on percentages and total numbers of T and NK cells; in the early posttransplant phase, NK cells were predominant and ch14.18 was superior, whereas later on, T cells represented the majority of immune cells and NG-CU was more effective. Our study highlights the importance of analyzing effector cell subsets in patients before initiating antibody-based therapy. Consequently, we propose an adjusted administration of both antibody constructs, considering the state of posttransplant immune recovery, to optimize anti-tumor activity.
(© 2023. The Author(s).)
Databáze: MEDLINE
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