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- Gao, Y, et al.
(författare)
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Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variant
- 2022
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 28:3, s. 472-
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Tidskriftsartikel (refereegranskat)abstract
- The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant of concern (VOC) has destabilized global efforts to control the impact of coronavirus disease 2019 (COVID-19). Recent data have suggested that B.1.1.529 can readily infect people with naturally acquired or vaccine-induced immunity, facilitated in some cases by viral escape from antibodies that neutralize ancestral SARS-CoV-2. However, severe disease appears to be relatively uncommon in such individuals, highlighting a potential role for other components of the adaptive immune system. We report here that SARS-CoV-2 spike-specific CD4+ and CD8+ T cells induced by prior infection or BNT162b2 vaccination provide extensive immune coverage against B.1.1.529. The median relative frequencies of SARS-CoV-2 spike-specific CD4+ T cells that cross-recognized B.1.1.529 in previously infected or BNT162b2-vaccinated individuals were 84% and 91%, respectively, and the corresponding median relative frequencies for SARS-CoV-2 spike-specific CD8+ T cells were 70% and 92%, respectively. Pairwise comparisons across groups further revealed that SARS-CoV-2 spike-reactive CD4+ and CD8+ T cells were functionally and phenotypically similar in response to the ancestral strain or B.1.1.529. Collectively, our data indicate that established SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses, especially after BNT162b2 vaccination, remain largely intact against B.1.1.529.
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- Ghaderi, A, et al.
(författare)
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A ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells
- 2022
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:10
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Tidskriftsartikel (refereegranskat)abstract
- The receptor tyrosine kinase orphan receptor 1 (ROR1) is absent in most normal adult tissues but overexpressed in various malignancies and is of importance for tumor cell survival, proliferation, and metastasis. In this study, we evaluated the apoptotic effects of a novel small molecule inhibitor of ROR1 (KAN0441571C) as well as venetoclax (BCL-2 inhibitor), bendamustine, idelalisib (PI3Kδ inhibitor), everolimus (mTOR inhibitor), and ibrutinib (BTK inhibitor) alone or in combination in human MCL primary cells and cell lines. ROR1 expression was evaluated by flow cytometry and Western blot (WB). Cytotoxicity was analyzed by MTT and apoptosis by Annexin V/PI staining as well as signaling and apoptotic proteins (WB). ROR1 was expressed both in patient-derived MCL cells and human MCL cell lines. KAN0441571C alone induced significant time- and dose-dependent apoptosis of MCL cells. Apoptosis was accompanied by decreased expression of MCL-1 and BCL-2 and cleavage of PARP and caspase 3. ROR1 was dephosphorylated as well as ROR1-associated signaling pathway molecules, including the non-canonical WNT signaling pathway (PI3Kδ/AKT/mTOR). The combination of KAN0441571C and ibrutinib, venetoclax, idelalisib, everolimus, or bendamustine had a synergistic apoptotic effect and significantly prevented phosphorylation of ROR1-associated signaling molecules as compared to KAN0441571C alone. Our results suggest that targeting ROR1 by a small molecule inhibitor, KAN0441571C, should be further evaluated particularly in combination with other targeting drugs as a new therapeutic approach for MCL.
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- Ghaderi, A, et al.
(författare)
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ROR1 Is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells
- 2020
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- The receptor tyrosine kinase ROR1 is absent in most normal adult tissues, but overexpressed in several malignancies. In this study, we explored clinical and functional inhibitory aspects of ROR1 in diffuse large B-cell lymphoma (DLBCL). ROR1 expression in tumor cells was more often observed in primary refractory DLBCL, Richter’s syndrome and transformed follicular lymphoma than in relapsed and non-relapsed DLBCL patients (p < 0.001). A survival effect of ROR1 expression was preliminarily observed in relapsed/refractory patients independent of gender and stage but not of age, cell of origin and international prognostic index. A second generation small molecule ROR1 inhibitor (KAN0441571C) induced apoptosis of ROR1+ DLBCL cell lines, similar to venetoclax (BCL-2 inhibitor) but superior to ibrutinib (BTK inhibitor). The combination of KAN0441571C and venetoclax at EC50 concentrations induced almost complete killing of DLBCL cell lines. Apoptosis was accompanied by the downregulation of BCL-2 and MCL-1 and confirmed by the cleavage of PARP and caspases 3, 8, 9. PI3Kδ/AKT/mTOR (non-canonical Wnt pathway) as well as β-catenin and CK1δ (canonical pathway) were inactivated. In zebra fishes transplanted with a ROR1+ DLBCL cell line, KAN0441571C induced a significant tumor reduction. New drugs with mechanisms of action other than those available for DLBCL are warranted. ROR1 inhibitors might represent a novel promising approach.
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- Mikaelsson, E, et al.
(författare)
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Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell chronic lymphocytic leukemia and mantle cell lymphoma
- 2005
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 105:12, s. 4828-4835
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Tidskriftsartikel (refereegranskat)abstract
- Fibromodulin is an extracellular matrix protein normally produced by collagen-rich tissues; the fibromodulin gene has been found to be the most overexpressed gene in B-cell chronic lymphocytic leukemia. In this study, fibromodulin was expressed at the gene level (reverse transcription-polymerase chain reaction [RT-PCR]) in all patients with B-CLL (n = 75) and in most (5 of 7) patients with mantle cell lymphoma (MCL). No mutations in the fibromodulin gene were detected. Fibromodulin was also detected at the protein level in the cytoplasm of the B-CLL cells and in the supernatant after in vitro cultivation, but not at the cell surface. Fibromodulin was not found in patients with T-cell chronic lymphocytic leukemia (T-CLL), B-cell prolymphocytic leukemia (B-PLL), T-cell prolymphocytic leukemia (T-PLL), hairy cell leukemia, follicular lymphoma, lymphoplasmacytic lymphoma, multiple myeloma, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), or chronic myelogenous leukemia (CML) or in 36 hematologic cell lines. Normal blood mononuclear cells (T and B lymphocytes, monocytes), tonsil B cells, and granulocytes did not express fibromodulin. Activation (phorbol 12-myristate 13-acetate [PMA]/ionomycin) of normal T and B lymphocytes induced weak fibromodulin gene expression, but not to the extent seen in freshly isolated B-CLL cells. The reason for the exclusive ectopic expression of fibromodulin in B-CLL and MCL is unknown. However, its unique protein expression makes it likely that fibromodulin is involved in the pathobiology of B-CLL and MCL. (Blood. 2005;105:4828-4835)
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- Tam, CS, et al.
(författare)
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Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion
- 2021
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 106:9, s. 2354-2363
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Tidskriftsartikel (refereegranskat)abstract
- Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 – 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 – 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 – 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.
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