183 research outputs found
Multispecific Aspergillus T Cells Selected by CD137 or CD154 Induce Protective Immune Responses Against the Most Relevant Mold Infections
Background.âAspergillus and Mucorales species cause severe infections in patients after hematopoietic stem cell transplantation (HSCT). Induction of antifungal CD4+ T-helper type 1 (Th1) immunity is an appealing strategy to combat these infections. Immunotherapeutic approaches are so far limited because of a lack of antigens inducing protective T cells, their elaborate production, and the need of targeting a broad spectrum of pathogenic fungi. Methods.âWe examined the response to different Aspergillus fumigatus proteins in healthy individuals and patients after HSCT and compared rapid selection protocols for fungus-specific T cells based on CD137 or CD154 expression. Results.âThe A. fumigatus proteins Crf1, Gel1, and Pmp20 induced strong Th1 responses in healthy individuals. T cells specific for these antigens expanded in patients with active invasive aspergillosis, indicating their contribution to infection control. Th1 cells specific for the 3 proteins can be selected with similar specificity within 24 hours, based on CD137 or CD154 expression. These cells recognize naturally processed A. fumigatus and the multispecific T-cell lines, directed against all 3 proteins, especially those selected by CD154, additionally cross-react to different Aspergillus and Mucorales species. Conclusions.âThese findings may form the basis for adoptive T-cell transfer for prophylaxis or treatment in patients with these devastating infection
Restoration of CD28 Expression in CD28â CD8+ Memory Effector T Cells Reconstitutes Antigen-induced IL-2 Production
The control of many persistent viral infections by Ag-specific cytolytic CD8+ T cells requires a concurrent virus-specific CD4+ Th cell response. This reflects in part a requirement of activated effector CD8+ T cells for paracrine IL-2 production as a growth and survival factor. In human CMV and HIV infection, the majority of differentiated virus-specific CD8+ T cells notably lose the ability to produce IL-2 but also lose expression of CD28, a costimulatory molecule. Analysis of the fraction of memory CD8+ T cells that continue to express CD28 revealed these cells retain the ability to produce IL-2. Therefore, we examined if IL-2 production by CD28â CD8+ T cells could be restored by introduction of a constitutively expressed CD28 gene. Expression of CD28 in CD28â CD8+ CMV- and HIV-specific CD8+ T cells reconstituted the ability to produce IL-2, which could sustain an autocrine proliferative response after Ag recognition. These results suggest that the loss of CD28 expression during differentiation of memory/effector CD8+ T cells represents a decisive step in establishing regulation of responding CD8+ T cells, increasing the dependence on CD4+ Th for proliferation after target recognition, and has implications for the treatment of viral disease with adoptively transferred CD8+ T cells
Chemokine receptorâtargeted PET/CT provides superior diagnostic performance in newly diagnosed marginal zone lymphoma patients: a head-to-head comparison with [18F]FDG
Background
In patients with marginal zone lymphoma (MZL), [18F]FDG PET/CT provided inconsistent diagnostic accuracy. C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in MZL and thus, may emerge as novel theranostic target. We aimed to evaluate the diagnostic performance of CXCR4-targeting [68Ga]Ga-PentixaFor when compared to [18F]FDG PET/CT in MZL.
Methods
Thirty-two untreated MZL patients (nodal, n = 17; extranodal, n = 13; splenic, n = 2) received [68Ga]Ga-PentixaFor and [18F]FDG PET/CT within median 2 days. We performed a visual and quantitative analysis of the total lymphoma volume by measuring maximum/peak standardized uptake values (SUVmax/peak), and calculating target-to-background ratios (TBR, defined as lesion-based SUVpeak divided by SUVmean from blood pool). Visual comparisons for both radiotracers were carried out for all target lesions (TL), and quantitative analysis of concordant TL evident on both scans. Last, MZL subtype analyses were also conducted.
Results
On a patient-based level, [68Ga]Ga-PentixaFor identified MZL manifestations in 32 (100%) subjects (vs. [18F]FDG, 25/32 [78.1%]). Of the 256 identified TL, 127/256 (49.6%) manifestations were evident only on CXCR4-directed imaging, while only 7/256 (2.7%) were identified on [18F]FDG but missed by [68Ga]Ga-PentixaFor. In the remaining 122/256 (47.7%) concordant TL, [68Ga]Ga-PentixaFor consistently provided increased metrics when compared to [18F]FDG: SUVmax, 10.3 (range, 2.53â37.2) vs. 5.72 (2.32â37.0); SUVpeak, 6.23 (1.58â25.7) vs. 3.87 (1.54â27.7); P < 0.01, respectively. Concordant TL TBR on [68Ga]Ga-PentixaFor (median, 3.85; range, 1.05â16.0) was also approximately 1.8-fold higher relative to [18F]FDG (median, 2.08; range, 0.81â28.8; P < 0.01). Those findings on image contrast, however, were driven by nodal MZL (P < 0.01), and just missed significance for extranodal MZL (P = 0.06).
Conclusions
In newly diagnosed MZL patients, [68Ga]Ga-PentixaFor identified more sites of disease when compared to [18F]FDG, irrespective of MZL subtype. Quantitative PET parameters including TBR were also higher on [68Ga]Ga-PentixaFor PET/CT, suggesting improved diagnostic read-out using chemokine receptor-targeted imaging
Follow-up of the GHSG HD16 trial of PET-guided treatment in early-stage favorable Hodgkin lymphoma.
The primary analysis of the GHSG HD16 trial indicated a significant loss of tumor control with PET-guided omission of radiotherapy (RT) in patients with early-stage favorable Hodgkin lymphoma (HL). This analysis reports long-term outcomes. Overall, 1150 patients aged 18-75 years with newly diagnosed early-stage favorable HL were randomized between standard combined-modality treatment (CMT) (2x ABVD followed by PET/CT [PET-2] and 20 Gy involved-field RT) and PET-2-guided treatment omitting RT in case of PET-2 negativity (Deauville score [DS]â<â3). The study aimed at excluding inferiority of PET-2-guided treatment and assessing the prognostic impact of PET-2 in patients receiving CMT. At a median follow-up of 64 months, PET-2-negative patients had a 5-year progression-free survival (PFS) of 94.2% after CMT (nâ=â328) and 86.7% after ABVD alone (nâ=â300; HRâ=â2.05 [1.20-3.51]; pâ=â0.0072). 5-year OS was 98.3% and 98.8%, respectively (pâ=â0.14); 4/12 documented deaths were caused by second primary malignancies and only one by HL. Among patients assigned to CMT, 5-year PFS was better in PET-2-negative (nâ=â353; 94.0%) than in PET-2-positive patients (nâ=â340; 90.3%; pâ=â0.012). The difference was more pronounced when using DS4 as cut-off (DS 1-3: nâ=â571; 94.0% vs. DSââ„â4: nâ=â122; 83.6%; pâ<â0.0001). Taken together, CMT should be considered standard treatment for early-stage favorable HL irrespective of the PET-2-result
Hematopoietic stem cell involvement in BCR-ABL1-positive ALL as a potential mechanism of resistance to blinatumomab therapy
The bispecific T-cell engager blinatumomab targeting CD19 can induce complete remission in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, some patients ultimately relapse with loss of CD19 antigen on leukemic cells, which has been established as a novel mechanism to escape CD19-specific immunotherapies. Here, we provide evidence that CD19-negative (CD19â) relapse after CD19-directed therapy in BCP-ALL may be a result of the selection of preexisting CD19â malignant progenitor cells. We present 2 BCR-ABL1 fusionâpositive BCP-ALL patients with CD19â myeloid lineage relapse after blinatumomab therapy and show BCR-ABL1 positivity in their hematopoietic stem cell (HSC)/progenitor/myeloid compartments at initial diagnosis by fluorescence in situ hybridization after cell sorting. By using the same approach with 25 additional diagnostic samples from patients with BCR-ABL1âpositive BCP-ALL, we identified HSC involvement in 40% of the patients. Patients (6 of 8) with major BCR-ABL1 transcript encoding P210BCR-ABL1 mainly showed HSC involvement, whereas in most of the patients (9 of 12) with minor BCR-ABL1 transcript encoding P190BCR-ABL1, only the CD19+ leukemia compartments were BCR-ABL1 positive (P = .02). Our data are of clinical importance, because they indicate that both CD19+ cells and CD19â precursors should be targeted to avoid CD19â relapses in patients with BCR-ABL1âpositive ALL
Measurement of Ï production in pp collisions at âs = 2.76 TeV
The production of Ï(1S), Ï(2S) and Ï(3S)
mesons decaying into the dimuon final state is studied with
the LHCb detector using a data sample corresponding to an
integrated luminosity of 3.3 pbâ1 collected in protonâproton
collisions at a centre-of-mass energy of âs = 2.76 TeV. The
differential production cross-sections times dimuon branching
fractions are measured as functions of the Ï transverse
momentum and rapidity, over the ranges pT < 15 GeV/c
and 2.0 < y < 4.5. The total cross-sections in this kinematic
region, assuming unpolarised production, are measured to be
Ï (pp â Ï(1S)X) Ă B
Ï(1S)âÎŒ+ÎŒâ
= 1.111 ± 0.043 ± 0.044 nb,
Ï (pp â Ï(2S)X) Ă B
Ï(2S)âÎŒ+ÎŒâ
= 0.264 ± 0.023 ± 0.011 nb,
Ï (pp â Ï(3S)X) Ă B
Ï(3S)âÎŒ+ÎŒâ
= 0.159 ± 0.020 ± 0.007 nb,
where the first uncertainty is statistical and the second systematic
Multispecific Aspergillus T cells selected by CD137 or CD154 induce protective immune responses against the most relevant mold infections
BACKGROUND: Aspergillus and Mucorales species cause severe infections in patients after hematopoietic stem cell transplantation (HSCT). Induction of antifungal CD4(+) T-helper type 1 (Th1) immunity is an appealing strategy to combat these infections. Immunotherapeutic approaches are so far limited because of a lack of antigens inducing protective T cells, their elaborate production, and the need of targeting a broad spectrum of pathogenic fungi. METHODS: We examined the response to different Aspergillus fumigatus proteins in healthy individuals and patients after HSCT and compared rapid selection protocols for fungus-specific T cells based on CD137 or CD154 expression. RESULTS: The A. fumigatus proteins Crf1, Gel1, and Pmp20 induced strong Th1 responses in healthy individuals. T cells specific for these antigens expanded in patients with active invasive aspergillosis, indicating their contribution to infection control. Th1 cells specific for the 3 proteins can be selected with similar specificity within 24 hours, based on CD137 or CD154 expression. These cells recognize naturally processed A. fumigatus and the multispecific T-cell lines, directed against all 3 proteins, especially those selected by CD154, additionally cross-react to different Aspergillus and Mucorales species. CONCLUSIONS: These findings may form the basis for adoptive T-cell transfer for prophylaxis or treatment in patients with these devastating infections
Distinct and complementary roles for Aspergillus fumigatus-specific Tr1 and regulatory T cells in humans and mice
Unlike induced regulatory T cells ( ) that have been shown to play an essential role in the development of protective immunity to the ubiquitous mold Aspergillus fumigatus, type-(1)-regulatory T cells (Tr1) cells have, thus far, not been implicated in this process. Here, we evaluated the role of Tr1 cells specific for an epitope derived from the cell wall glucanase Crf-1 of A. fumigatus (Crf-1/p41) in antifungal immunity. We identified Crf-1/p41-specific latent-associated Tr1 cells in healthy humans and mice after vaccination with Crf-1/p41+zymosan. These cells produced high amounts of interleukin (IL)-10 and suppressed the expansion of antigen-specific T cells in vitro and in vivo. In mice, in vivo differentiation of Tr1 cells was dependent on the presence of the aryl hydrocarbon receptor, c-Maf and IL-27. Moreover, in comparison to Tr1 cells, that recognize the same epitope were induced in an interferon gamma-type inflammatory environment and more potently suppressed innate immune cell activities. Overall, our data show that Tr1 cells are involved in the maintenance of antifungal immune homeostasis, and most likely play a distinct, yet complementary, role compared with
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Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors
Neurologic events (NEs) have been reported during treatment with blinatumomab, a bispecific T cell engager (BiTEÂź) construct. We evaluated the occurrence, severity, and management of NEs; the relationship between NEs and blinatumomab dose; and the potential clinical risk factors in an open-label, single-arm, phase 2 study (Nâ=â189). Patients had Philadelphia chromosome-negative, relapsed/refractory acute lymphoblastic leukemia (ALL) and â„â10% bone marrow blasts. The relationship between blinatumomab exposure and NE incidence and severity was assessed. Clinical risk factors for NEs were assessed in a post hoc multivariate analysis. Overall, 98 patients (52%) experienced NEs: most frequently, dizziness, tremor, confusional state, and encephalopathy. NEs occurred predominantly during cycle 1 (median onset, 9 days) and were usually grades 1 or 2. Grade â„â3 NEs (13-17% incidence), serious NEs (16-19% incidence), and recurring NEs were managed with infusion interruptions or dexamethasone treatment. The incidence of NEs increased with increasing blinatumomab exposure at a given dose, but exposure appeared unrelated to NE severity. NEs were more frequent in patients â„â65 years than <â65 years (72 vs 49%). In a multivariate analysis, race other than white (hazard ratio [HR], 2.11; Pâ=â0.009), >â2 prior salvage therapies (HR, 2.48; Pâ=â0.006), and prior NEs (HR, 1.65; Pâ=â0.020) were risk factors for time to first on-study NE. Although the mechanism underlying NEs associated with blinatumomab treatment in patients with relapsed/refractory ALL remains unclear, NEs tended to occur early during treatment and were often resolved by interrupting treatment and with dexamethasone. Additional research is warranted to investigate the risk factors for NEs
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