| 1. |
- Andersson, Maria, et al.
(författare)
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Local and Systemic Immunity During Five Vaccinations Against SARS-CoV-2 in Zanubrutinib-Treated Patients With Chronic Lymphocytic Leukemia
- 2023
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Ingår i: Journal of Hematology. - : Elmer Press, Inc.. - 1927-1212 .- 1927-1220. ; 12:4, s. 170-175
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with chronic lymphocytic leukemia (CLL) are vulnerable to coronavirus disease 2019 (COVID-19) and are at risk of inferior response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, especially if treated with the first-generation Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib. We aimed to evaluate the impact of the third-generation BTKi, zanubrutinib, on systemic and mucosal response to SARS-CoV-2 vaccination.Methods: Nine patients with CLL with ongoing zanubrutinib therapy were included and donated blood and saliva during SARS-CoV-2 vaccination, before vaccine doses 3 and 5 and 2 - 3 weeks after doses 3, 4, and 5. Ibrutinib-treated control patients (n = 7) and healthy aged-matched controls (n = 7) gave blood 2 - 3 weeks after vaccine dose 5. We quantified reactivity and neutralization capacity of SARS-CoV-2-specific IgG and IgA antibodies (Abs) in both serum and saliva, and reactivity of T cells activated with viral peptides.Results: Both zanubrutinib- and ibrutinib-treated patients had significantly, up to 1,000-fold, lower total spike-specific Ab levels after dose 5 compared to healthy controls (P < 0.01). Spike-IgG levels in serum from zanubrutinib-treated patients correlated well to neutralization capacity (r = 0.68; P < 0.0001) and were thus functional. Mucosal immunity (specific IgA in serum and saliva) was practically absent in zanubrutinib-treated patients even after five vaccine doses, whereas healthy controls had significantly higher levels (tested in serum after vaccine dose 5) (P < 0.05). In contrast, T-cell reactivity against SARS-CoV-2 peptides was equally high in zanubrutinib- and ibrutinib-treated patients as in healthy control donors.Conclusions: In our small cohort of zanubrutinib-treated CLL patients, we conclude that up to five doses of SARS-CoV-2 vaccination induced no detectable IgA mucosal immunity, which likely will impair the primary barrier defence against the infection. Systemic IgG responses were also impaired, whereas T-cell responses were normal. Further and larger studies are needed to evaluate the impact of these findings on disease protection.
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| 2. |
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| 3. |
- Hojjat-Farsangi, Mohammad, et al.
(författare)
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The tyrosine kinase receptor ROR1 is constitutively phosphorylated in chronic lymphocytic leukemia (CLL) cells
- 2013
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Ingår i: PLOS ONE. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1932-6203.
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylation of receptor tyrosine kinases (RTKs) has a key role in cellular functions contributing to the malignant phenotype of tumor cells. We and others have previously demonstrated that RTK ROR1 is overexpressed in chronic lymphocytic leukemia (CLL). Silencing siRNA downregulated ROR1 and induced apoptosis of CLL cells. In the present study we analysed ROR1 isoforms and the phosphorylation pattern in CLL cells (n=38) applying western blot and flow-cytometry using anti-ROR1 antibodies and an anti-phospho-ROR1 antibody against the TK domain. Two major ROR1 bands with the size of 105 and 130 kDa respectively were identified, presumably representing unglycosylated (immature) and glycosylated (mature) ROR1 respectively as well as a 260 kDa band which may represent dimerized ROR1. A ROR1 band of 64 kDa that may correspond to a C-terminal fragment was also noted, present only in the nucleus. The 105 kDa ROR1 isoform was more frequently expressed in non-progressive as compared to progressive CLL patients (p=0.03). The 64, 105, 130 and 260 kDa bands were constitutively phosphorylated both at tyrosine and serine residues. Phosphorylation intensity of the mature (130 kDa) isoform was significantly higher in progressive than in non-progressive disease (p<0.001). Incubation of CLL cells with a mouse anti-ROR1 KNG or an anti-ROR1 CRD mAb respectively induced dephosphorylation of ROR1 before entering apoptosis. In conclusion CLL cells expressed different isoforms of ROR1 which were constitutively phosphorylated. The mature, phosphorylated ROR1 isoform was associated with a progressive disease stage. Targeting ROR1 by mAbs induced specific dephosphorylation and leukemic cell death. ROR1 might be an interesting therapeutic target.
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| 4. |
- Lagerlöf, Ingemar, et al.
(författare)
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Limited, But Not Eliminated, Excess Long-Term Morbidity in Stage I-IIA Hodgkin Lymphoma Treated With Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine and Limited-Field Radiotherapy
- 2022
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Ingår i: Journal of Clinical Oncology. - : Lippincott, Williams & Wilkins. - 0732-183X .- 1527-7755. ; 40:13, s. 1487-1496
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Balancing disease control and toxicity from chemotherapy and radiotherapy (RT) when treating early-stage classical Hodgkin lymphoma (cHL) is important. Available data on long-term toxicity after RT for cHL mostly refer to RT techniques no longer in use. We aimed to describe long-term toxicity from modern limited-field (LF)-RT after two or four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). PATIENTS AND METHODS This study included all patients with cHL treated with two or four cycles of ABVD and 30 Gy LF-RT during 1999-2005 in Sweden. Patients (n = 215) and comparators (n = 860), matched for age, gender, and region of residence, were cross-checked against national health registries for malignancies, diseases of the circulatory system (DCS), and diseases of the respiratory system (DRS) from the day of diagnosis of cHL. RESULTS The risk of a malignancy was higher for patients than comparators, hazard ratio (HR) 1.5 (95% CI, 1.0 to 2.4), as was the risk for DCS 1.5 (95% CI, 1.1 to 2.0) and for DRS 2.6 (95% CI, 1.6 to 4.3). The median followup was 16 years (range, 12-19 years). Of individual diagnoses in DCS, only venous thromboembolism was statistically significantly elevated. If the first 6 months (ie, time of active treatment for cHL) were excluded and censoring at relapse of cHL or diagnosis of any malignancy, the increased HR for venous thromboembolism diminished. Most of the excess risk for DRS consisted of asthma, HR 3.5 (95% CI, 1.8 to 6.8). Patients diagnosed with DRS were significantly younger than comparators. CONCLUSION Compared with toxicity from earlier RT techniques, excess morbidity was not eliminated, but lower than previously reported. The elevated risk of DRS was driven by diagnosis of asthma, which could in part be explained by misdiagnosis of persisting pulmonary toxicity.
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| 5. |
- Lagerlöf, Ingemar, et al.
(författare)
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No excess long-term mortality in stage I-IIA Hodgkin lymphoma patients treated with ABVD and limited field radiotherapy
- 2020
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Ingår i: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 188:5, s. 685-691
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Tidskriftsartikel (refereegranskat)abstract
- When treating limited stage classical Hodgkin lymphoma (cHL), balancing treatment efficacy and toxicity is important. Toxicities after extended-field radiotherapy are well documented. Investigators have aimed at reducing toxicity without compromising efficacy, mainly by using combined modality treatment (CMT), i.e. chemotherapy and limited-field radiotherapy. In some clinical trials, radiotherapy has been omitted. We evaluated 364 patients with stage I-IIA cHL treated between 1999 and 2005. Patients were treated with two or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) according to presence of risk factors, followed by 30 Gy limited-field (reduced compared to involved-field) radiotherapy. After a median follow-up of 16 years for survival, freedom from progression at five and ten years was 93% and overall survival at 5 and 10 years was 98% and 96%, respectively. Only two relapses, out of 27, occurred after more than 5 years. There was no excess mortality compared to the general population. Of the analysed subgroups, only patients with progression within five years showed significant excess mortality. The absence of excess mortality questions the concept of omitting radiotherapy after short-term chemotherapy, a strategy that has been associated with an elevated risk of relapse but not yet with a proven reduced long-term excess mortality.
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| 6. |
- Palma, Marzia, et al.
(författare)
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Ibrutinib induces rapid down-regulation of inflammatory markers and altered transcription of chronic lymphocytic leukaemia-related genes in blood and lymph nodes
- 2018
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Ingår i: British Journal of Haematology. - : WILEY. - 0007-1048 .- 1365-2141. ; 183:2, s. 212-224
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Tidskriftsartikel (refereegranskat)abstract
- In chronic lymphocytic leukaemia (CLL) patients, treatment with the Bruton tyrosine kinase inhibitor ibrutinib induces a rapid shift of tumour cells from lymph nodes (LN) to peripheral blood (PB). Here, we characterized in depth the dynamics of ibrutinib-induced inflammatory, transcriptional and cellular changes in different compartments immediately after treatment initiation in seven relapsed/refractory CLL patients. Serial PB and LN samples were taken before start and during the first 29 days of treatment. Changes in plasma inflammation-related biomarkers, CLL cell RNA expression, B-cell activation and migration markers expression, and PB mononuclear cell populations were assessed. A significant reduction of 10 plasma inflammation markers, the majority of which were chemokines and not CLL-derived, was observed within hours, and was paralleled by very early increase of CD19(+) circulating cells. At the RNA level, significant and continuous changes in transcription factors and signalling molecules linked to B-cell receptor signalling and CLL biology was observed in both PB and LN CLL cells already after 2 days of treatment. In conclusion, ibrutinib seems to instantly shut off an ongoing inflammatory response and interfere with diverse sensitive pathways in the LN.
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| 7. |
- Palma, Marzia
(författare)
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Immunological and molecular studies for the development of vaccine therapy for chronic lymphocytic leukemia
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic lymphocytic leukaemia (CLL) is a malignant lymphoproliferative disorder which typically affects elderly people. It is the commonest leukemia in the Western adults, accounting for 25-30% of all leukemias and for 10% of all hematological neoplasms. Although new modalities such as combination therapy with fludarabine, cyclophosphamide (CTX) and the anti-CD20 antibody rituximab have greatly improved clinical outcome in a fraction of patients, CLL is largely considered incurable and there is a continuous need to develop new treatment strategies. Anti-cancer active specific immunotherapy aims at activating the patient's immune system to recognize and eliminate the tumor. A number of clinical observations as well as several preclinical studies indicate that CLL is responsive to immune effector functions. In the first part of this thesis, we investigated the ability of a promiscuous HLA class II epitope, hTERT (611 626) (GV1001) to elicit antileukemic immune responses in vitro. We demonstrated that CLL patients with hTERT-expressing leukemic cells have naturally occurring hTERT-specific T cells that proliferate and can be expanded in vitro and used to lyse autologous CLL cells. We therefore identified telomerase as a vaccine candidate in CLL. We then analyzed hTERT mRNA splicing patterns in CLL by a newly designed quantitative PCR assay and showed that the expression of the functional transcript of hTERT (hTERT-FL) is independent from disease phase in IgHV mutated but not in unmutated patients. This finding highlights the necessity of focusing on this transcript when analyzing hTERT expression and encourages further studies to assess whether hTERT-FL could generate novel epitopes that may serve as immunotherapy targets. In the second part of the thesis, we studied safety, immune and clinical effects of vaccination with autologous DC loaded with apoptotic CLL cells (Apo-DC) in CLL patients in a phase I clinical trial. Using a combination of leukapheresis and affinity-based technologies (CliniMACS®) for monocyte enrichment, we were able to produce a sufficient amount of DC vaccine that met accepted and established quality criteria. Sixteen patients were accrued stepwise in three different cohorts receiving Apo-DC alone, Apo-DC + granulocyte-macrophage-colony-stimulating-factor (GM-CSF), or Apo-DC + GM-CSF + low-dose CTX. Vaccination was well tolerated and increased leukemia-specific immunity in 10/15 (66%) of the patients (2/5, 3/5 and 5/5 in the three cohorts, respectively). No significant difference in time-to progression (TTP) between immuneresponders and non-immune responders was observed. An additional patient was immunized repeatedly for a long period of time and achieved a complete response in blood and a nodular partial response in bone marrow. CD4+CD25highFOXP3+ regulatory T-cells (Tregs) measured in one year follow-up period were significantly lower in immuneresponders vs non-responders (p<0.0001). In this study, we demonstrated that vaccination with Apo-DC is a feasible approach that can generate immune responses and potentially clinical responses and that combination with GM-CSF and low-dose CTX functions as an immunological adjuvant in this setting. In conclusion, the studies presented in this thesis suggest that immunotherapy is a promising approach in CLL and promote further investigation to better define the vaccination strategy and combination with immune enhancing/modulating drugs which holds the greatest potential to generate immune responses and clinical benefit in CLL patients.
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| 8. |
- Palma, Marzia, et al.
(författare)
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T Cells In Chronic Lymphocytic Leukemia Display Dysregulated Expression Of Immune Checkpoints And Activation Markers
- 2017
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 102:3, s. 562-572
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Tidskriftsartikel (refereegranskat)abstract
- Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3+ cells and the CD8+ subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4+ and CD8+ cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients (P=0.0003 and P=0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4+ and CD8+ subsets, with a significantly higher PD-1 expression. Higher numbers of CD4+ and CD8+ cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67+) and activated (CD69+) CD4+ and CD8+ cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls (P<0.05), albeit decreasing to low levels in pre-treated patients. In conclusion, chronic lymphocytic leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways.
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| 9. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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