Rational design of PD-1-CD28 immunostimulatory fusion proteins for CAR T cell therapy.

Autor: Lorenzini T; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Cadilha BL; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Obeck H; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Benmebarek MR; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany.; National Cancer Institute (NCI), Bethesda, MD, USA., Märkl F; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Michaelides S; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Strzalkowski T; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Briukhovetska D; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Müller PJ; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Nandi S; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Winter P; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Majed L; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Grünmeier R; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Seifert M; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Rausch S; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany., Feuchtinger T; Department of Pediatric Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Dr. von Hauner University Children's Hospital, LMU University Hospital, LMU, Munich, Germany.; German Center for Infection Research (DZIF), Munich, Germany., Endres S; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany.; German Center for Translational Cancer Research (DKTK), partner site Munich, Munich, Germany.; Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany., Kobold S; Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, LMU Munich, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany. sebastian.kobold@med.uni-muenchen.de.; German Center for Translational Cancer Research (DKTK), partner site Munich, Munich, Germany. sebastian.kobold@med.uni-muenchen.de.; Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany. sebastian.kobold@med.uni-muenchen.de.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2023 Sep; Vol. 129 (4), pp. 696-705. Date of Electronic Publication: 2023 Jul 04.
DOI: 10.1038/s41416-023-02332-9
Abstrakt: Background: In many situations, the therapeutic efficacy of CAR T cells is limited due to immune suppression and poor persistence. Immunostimulatory fusion protein (IFP) constructs have been advanced as a tool to convert suppressive signals into stimulation and thus promote the persistence of T cells, but no universal IFP design has been established so far. We now took advantage of a PD-1-CD28 IFP as a clinically relevant structure to define key determinants of IFP activity.
Methods: We compared different PD-1-CD28 IFP variants in a human leukemia model to assess the impact of distinctive design choices on CAR T cell performance in vitro and a xenograft mouse model.
Results: We observed that IFP constructs that putatively exceed the extracellular length of PD-1 induce T-cell response without CAR target recognition, rendering them unsuitable for tumour-specific therapy. IFP variants with physiological PD-1 length ameliorated CAR T cell effector function and proliferation in response to PD-L1 + tumour cells in vitro and prolonged survival in vivo. Transmembrane or extracellular CD28 domains were found to be replaceable by corresponding PD-1 domains for in vivo efficacy.
Conclusion: PD-1-CD28 IFP constructs must mimic the physiological interaction of PD-1 with PD-L1 to retain selectivity and mediate CAR-conditional therapeutic activity.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: