Augmenting anti-CD19 and anti-CD22 CAR T-cell function using PD-1-CD28 checkpoint fusion proteins
Year: 2021
Type: article
Abstract: Despite high initial responses after treatment with anti-CD19 chimeric antigen receptor (CAR) T cells in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), 40–50% of patients relapse within 24 months 1 , 2 . In solid tumors, PD-1/-L1 (programmed death (ligand) 1) blockade enhances, i.e., Her2-specific CAR function 3 . Although BCP-ALL and bone marrow T cells express PD-L1/PD-1 4 , 5 , clinical benefit of PD-1/PD-L1-blocking antibodies is low and this mechanism in BCP-ALL remains controversial. Furthermore, PD-1/PD-L1-blocking antibodies trigger autoimmune side effects by uncontrolled T-cell proliferation of auto-reactive T cells. An attractive targeted alternative are synthetic fusion proteins—receptors with extracellular and transmembrane domains of PD-1 that are fused to the intracellular domain of CD28 and thus turn PD-1-mediated inhibitory signals into CD28-mediated T-cell stimulation. Here, we systematically characterize a fully human PD-1-CD28 fusion protein in combination with anti-CD19 and anti-CD22 CAR T cells. Aim of this study is to create an adaptable system to specifically increase functionality of anti-leukemia CAR T cells in order to protect CAR T cells from leukemia-induced inhibition.
Source: Blood Cancer Journal
Institutions: LMU Klinikum, Ludwig-Maximilians-Universität München, Center for Integrated Protein Science Munich, German Center for Infection Research, Stanford Medicine, Stanford Cancer Institute, Stanford University, Technical University of Munich, Deutsches Konsortium für Translationale Krebsforschung
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,480
Funders: Melanoma Research Alliance, Deutsches Krebsforschungszentrum, Deutsches Zentrum für Infektionsforschung, European Commission, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Jung-Stiftung für Wissenschaft und Forschung, Ludwig-Maximilians-Universität München, Deutsche Krebshilfe, Deutschen Konsortium für Translationale Krebsforschung, Hector Stiftung, School of Medicine, Stanford University, Horizon 2020 Framework Programme, Elitenetzwerk Bayern, Stanford Cancer Institute, H2020 European Research Council
Awards: G1498952464, G1547250008, G1809379011, G1871007102, G2017605187, G2697625030, G2732160497, G3012168829, G3123765769, Armoring multifunctional T cells for cancer therapy, G384650587, G4577351232, G4937468798, G4963151808, Training Network for Optimizing Adoptive T cell Therapy of Cancer, G6346254517, Training Network for the Immunotherapy of Cancer, G6426401002, G6490401407, G6613626400, G7104823900, Bispecific antibodies and T cell activating proteins against melanoma, G7830241568, G8104534379, G8769216704, G8793094017
OpenAlex ID: W3165352013