Recent studies have underscored the importance of gamma-delta (γδ) T cells in mediating potent MHC-unrestricted cytotoxicity in numerous malignancies. Here, we analyzed Vδ1 and Vδ2 γδ T cell subsets in newly diagnosed chronic myeloid leukemia (CML) patients (n = 40) who had initiated tyrosine kinase inhibitor (TKI) therapy including imatinib (n = 22), nilotinib (n = 14) and dasatinib (n = 4). Patient peripheral blood samples were analyzed at diagnosis and monitored prospectively at 3, 6, 12 and 18 months post-TKI. γδ T cells isolated from healthy donors and CML patients were used against K562, LAMA-84 and KYO-1 cell lines and against primary CML cells in cytotoxicity assays. We found large expansions of Vδ1 and Vδ2 T cells in patients at diagnosis compared to age-matched healthy donors (n = 40) (p < 0.0001). The γδ T cell reconstitution in patients on imatinib and also on nilotinib showed significant reductions of Vδ1 T cell and Vδ2 T cell absolute counts at 3 months compared to diagnosis. Importantly, Vδ1 and Vδ2 T absolute cell counts remained at normal levels from 3 months throughout the follow-up. Next, we observed susceptibility to specific lysis of primary CML tumor cells by Vδ1 T cells from healthy donors. Furthermore, we determined inherent cytotoxic reactivity by autologous patients' Vδ1 T lymphocytes against primary CML tumor cells. Finally, the TCR clonality profiles showed in CML patients mostly polyclonal repertoires regardless of the TKI. Our results provide further evidence into γδ T cell antileukemia immunity in CML that might be beneficial for long-term disease control and treatment outcome.

• Klíčová slova
• Chronic myeloid leukemia, Clonality, Gamma-delta T cells, Tumor immunotherapy,
• MeSH
• buněčné linie MeSH
• chronická myeloidní leukemie * farmakoterapie   metabolismus   MeSH
• imatinib mesylát farmakologie   terapeutické užití   MeSH
• lidé MeSH
• myeloidní leukemie * metabolismus   MeSH
• receptory antigenů T-buněk gama-delta metabolismus   MeSH
• T-lymfocyty - podskupiny MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• imatinib mesylát MeSH
• receptory antigenů T-buněk gama-delta MeSH

Introduction We report the results of a phase I clinical trial NCT03790072 of an adoptive transfer of γδ T lymphocytes from haploidentical donors in patients with refractory/relapsed acute myeloid leukemia after lymphodepletion regimen. Patients and methods Healthy donor mononuclear cells collected by leukapheresis were consistently expanded to generate products of 109 to 1010 γδ T cells. Seven patients received donor-derived T cell product at doses of 106/kg (n = 3), 107/kg (n = 3), and 108/kg (n = 1). Results Four patients had bone marrow evaluation at day 28. One patient had a complete remission, one was classified as morphologic leukemia-free state, one had stable disease and one had no evidence of response. In one patient, there was evidence of disease control with repeat infusions up to 100 days after first dosing. There were no treatment-related serious adverse events or treatment-related Common Terminology Criteria for Adverse Events grade 3 or greater toxicities at any dose level. Allogeneic Vγ9Vδ2 T cell infusion was shown to be safe and feasible up to a cell dose of 108/kg. Discussion In agreement with previously published studies, the infusion of allogeneic Vγ9Vδ2 cells was safe. The contribution of lymphodepleting chemotherapy to responses seen cannot be ruled out. Main limitation of the study is the low number of patients and interruption due to COVID-19 pandemic. Conclusion These positive Phase 1 results support progression to phase II clinical trials.

• Klíčová slova
• Acute myeloid leukemia, Adoptive immunotherapy, Haploidentical donors, Phase I trial, γδ T cells,
• MeSH
• akutní myeloidní leukemie * terapie   MeSH
• COVID-19 * MeSH
• lidé MeSH
• pandemie MeSH
• T-lymfocyty MeSH
• transplantace hematopoetických kmenových buněk * metody   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• práce podpořená grantem MeSH

• MeSH
• akutní lymfatická leukemie diagnóza   etiologie   metabolismus   terapie   MeSH
• biologické markery MeSH
• biopsie MeSH
• dítě MeSH
• genová přestavba MeSH
• imunitní dozor * MeSH
• klonální evoluce genetika   imunologie   MeSH
• kostní dřeň MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• prekancerózy patologie   MeSH
• translokace genetická MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH