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Effects of the STAMP-inhibitor asciminib on T cell activation and metabolic fitness compared to tyrosine kinase inhibition by imatinib, dasatinib, and nilotinib.
Häselbarth, Lukas; Karow, Axel; Mentz, Kristin; Böttcher, Martin; Roche-Lancaster, Oisin; Krumbholz, Manuela; Jitschin, Regina; Mougiakakos, Dimitrios; Metzler, Markus.
Afiliação
  • Häselbarth L; Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany. lukas.haeselbarth@uk-erlangen.de.
  • Karow A; Comprehensive Cancer Center Erlangen-European Metropolitan Area Nuremberg (CCC-ER-EMN), Nuremberg, Germany. lukas.haeselbarth@uk-erlangen.de.
  • Mentz K; Interdisciplinary Centre for Clinical Research (IZKF), Erlangen, Germany. lukas.haeselbarth@uk-erlangen.de.
  • Böttcher M; Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Erlangen, Germany.
  • Roche-Lancaster O; Comprehensive Cancer Center Erlangen-European Metropolitan Area Nuremberg (CCC-ER-EMN), Nuremberg, Germany.
  • Krumbholz M; Interdisciplinary Centre for Clinical Research (IZKF), Erlangen, Germany.
  • Jitschin R; Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany.
  • Mougiakakos D; Department of Internal Medicine, Hematology and Oncology, University Hospital Magdeburg, Magdeburg, Germany.
  • Metzler M; Center of Medical Information and Communication Technology, University Hospital Erlangen, Erlangen, Germany.
Cancer Immunol Immunother ; 72(6): 1661-1672, 2023 Jun.
Article em En | MEDLINE | ID: mdl-36602564
ABSTRACT
T cell function is central to immune reconstitution and control of residual chronic myeloid leukemia (CML) cells after treatment initiation and is associated with achieving deep molecular response as a prerequisite for treatment-free remission, the ultimate therapeutic goal in CML. ATP-pocket-binding tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, and nilotinib are widely used for treating CML, but they have shown to inhibit T cell function as an "off-target" effect. Therefore, we tested asciminib, the first-in-class BCRABL1 fusion protein inhibitor specifically targeting the ABL myristoyl pocket (STAMP) and compared its effects on T cell function with imatinib, dasatinib, and nilotinib. Whereas all four TKIs inhibited the expression of the co-stimulatory protein CD28, the amino acid transporter CD98, proliferation, and secretion of pro-inflammatory cytokines IFNγ, IL-6, and IL-17A upon T cell stimulation, asciminib had less impact on PD-1, activation markers, and IL-2 secretion. T cells treated with asciminib and the other TKIs maintained their ability to mobilize their respiratory capacity and glycolytic reserve, which is an important surrogate for metabolic fitness and flexibility. Overall, we found milder inhibitory effects of asciminib on T cell activation, which might be beneficial for the immunological control of residual CML cells.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mielogênica Crônica BCR-ABL Positiva / Antineoplásicos Limite: Humans Idioma: En Revista: Cancer Immunol Immunother Assunto da revista: ALERGIA E IMUNOLOGIA / NEOPLASIAS / TERAPEUTICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mielogênica Crônica BCR-ABL Positiva / Antineoplásicos Limite: Humans Idioma: En Revista: Cancer Immunol Immunother Assunto da revista: ALERGIA E IMUNOLOGIA / NEOPLASIAS / TERAPEUTICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Alemanha