Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits ...clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.
Display omitted
•Identification of 1-18, a highly broad and potent VH1-46-derived CD4bs antibody•2.5-Å cryo-EM structure of 1-18-Env complex reveals inter-protomer contacts•1-18 overcomes VRC01-class resistance and restricts development of HIV-1 escape•Monotherapy with 1-18 maintains viral suppression in HIV-1YU2-infected humanized mice
Broadly neutralizing antibodies targeting the HIV-1 envelope protein are a promising option for prevention and treatment of HIV-1 infection. However, development of viral resistance can limit clinical efficacy. Schommers et al. identify a highly broad and potent antibody that targets the CD4 binding site of HIV-1. Compared with other potent CD4 binding site antibodies, it restricts the development of viral escape and effectively suppresses HIV-1 in vivo.
Patients undergoing allogeneic stem cell transplantation (allo-SCT) are given a real chance of cure, but at the same time are confronted with a considerable risk of mortality and of severe long-term ...impediments. This narrative, non-systematic literature review aims to describe the supportive and palliative care needs of allo-SCT recipients, including long-term survivors or those relapsing or dying after transplantation. It also evaluates the feasibility and effectivity of integrating palliative care early in transplant procedures. In this appraisal of available literature, the main findings relate to symptoms like fatigue and psychological distress, which appear to be very common in the whole allo-SCT trajectory and might even persist many years post-transplantation. Chronic GvHD has a major negative impact on quality of life. Overall, there is a paucity of research on further issues in the context of allo-SCT, like the distress related to the frequently unpredictable post-transplant trajectory and prognosis, as well as the end-of-life phase. First randomized controlled results support the effectiveness of early integration of specialized palliative care expertise into transplant algorithms. Barriers to this implementation are discussed.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a global health emergency. To improve the understanding of the systemic component of SARS-CoV-2, we investigated if viral load ...dynamics in plasma and respiratory samples are associated with antibody response and severity of coronavirus disease 2019 (COVID-19). SARS-CoV-2 RNA was found in plasma samples from 14 (44%) out of 32 patients. RNAemia was detected in 5 out of 6 fatal cases. Peak IgG values were significantly lower in mild/moderate than in severe (0.6 (interquartile range, IQR, 0.4-3.2) vs. 11.8 (IQR, 9.9-13.0), adjusted
= 0.003) or critical cases (11.29 (IQR, 8.3-12.0), adjusted
= 0.042). IgG titers were significantly associated with virus Ct (Cycle threshold) value in plasma and respiratory specimens ((ß = 0.4, 95% CI (confidence interval, 0.2; 0.5),
< 0.001 and ß = 0.5, 95% CI (0.2; 0.6),
= 0.002). A classification as severe or a critical case was additionally inversely associated with Ct values in plasma in comparison to mild/moderate cases (ß = -3.3, 95% CI (-5.8; 0.8),
= 0.024 and ß = -4.4, 95% CI (-7.2; 1.6),
= 0.007, respectively). Based on the present data, our hypothesis is that the early stage of SARS-CoV-2 infection is characterized by a primary RNAemia, as a potential manifestation of a systemic infection. Additionally, the viral load in plasma seems to be associated with a worse disease outcome.
Azacitidine combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and ...anti-leukemic properties we considered Lenalidomide to act synergistically with Azacitidine/DLI to improve outcome. We therefore prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of AML, MDS and CMML. Patients were scheduled for 8 cycles Azacitidine (75 mg/m2 day 1-7), Lenalidomide (2.5 or 5mg, day 1-21) and up to 3 DLI with increasing T cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of MDS (n=24), AML (n=23) or CMML (n=3) received a median of 7 (range, 1 to 8) cycles including 14 patients with 2.5mg and 36 with 5mg Lenalidomide daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lenalidomide dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in >10% of patients and modest acute (grade II-IV 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lenalidomide can be safely added to Azacitidine/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse. (NCT02472691).
To analyse patients with chronic ocular graft-versus-host disease (GvHD) under treatment with 100% autologous serum eye drops from a sealed manufacturing system.
17 patients with chronic ocular GvHD ...received 100% autologous serum eye drops from single use vials manufactured in a sealed system. Retrospective analysis included visual acuity, corneal staining, frequency of artificial tears, ocular symptoms by means of a questionnaire and information on subjective side effects and cost compensation.
Data of prior to autologous serum eye drops therapy and at a 6-month follow-up were obtained. They demonstrated a significant increase in visual acuity (logMAR oculus dexter/right eye (OD) 0.5±0.32 to 0.4±0.3; oculus sinister/left eye (OS) 0.6±0.35 to 0.3±0.35; p=0.177/0.003) and significant improvement in corneal staining (Oxford grading scheme: OD from 3±1.03 to 2±1.43, OS from 4±1.0 to 2±1.09, p=0.004/0.001) and ocular symptoms (ocular surface disease index: 88±20.59 to 63±22.77; p=0.02). Frequency of artificial tears was reduced and no side effects were reported. Patient satisfaction was 100%, and cost compensation by health insurance reached 80%.
100% autologous serum eye drops using a sealed manufacturing system were efficient in improving the ocular surface, patient symptoms and visual acuity without side effects. It seems to be safe to use 100% autologous serum despite earlier suspicions regarding immune complex accumulations and exacerbation of ocular surface inflammation. The potential effects of serum levels of systemic immunosuppressives through readministration onto the ocular surface need to be elucidated.
The prognosis of allogeneic stem cell transplant recipients admitted to the intensive care unit (ICU) has improved over the last decades. However, data focusing on patients treated in the ICU during ...the peri-transplant period are scarce. We therefore conducted an analysis comprising 70 patients who had allogeneic stem cell transplantation at the University Hospital Cologne between 2014 and 2020 and were admitted to the ICU between the initiation of conditioning therapy and day 30 after transplantation. The median age was 59 years (range: 18 − 72 years). 50% of patients were female. Sepsis was the most common cause for ICU admission (49%). Mechanical ventilation (MV) was required in 56% of patients, 27% had renal replacement therapy (RRT), and 64% needed vasopressors. The ICU, hospital, 90-day, and 1-year survival rates were 48.6%, 38.6%, 35.7%, and 16.2%, respectively. MV and/or RRT during the ICU stay were associated with an impaired survival (
p
< 0.0001). The same was true for the use of vasopressors (
p
< 0.0001). In contrast, baseline characteristics did not impact the outcome. Cardiopulmonary resuscitation (CPR) was performed in 17% of patients. None of the patients undergoing CPR was alive at 1 year. Among patients who died after discharge from the ICU (
n
= 23), sepsis and other infectious complications represented the major causes of death (48%). Taken together, the present analysis indicates unfavorable outcomes for allogeneic stem cell transplant recipients admitted to the ICU during the peri-transplant period. The data may help to make informed decisions with patients and their families.
Primary refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The FLAMSA-reduced intensity conditioning protocol (total body irradiation or treosulfan-based) has been ...described as an effective approach in patients with refractory leukemia undergoing allogeneic hematopoietic cell transplantation. A modified protocol (without amsacrine) has also recently been used. We retrospectively analyzed the transplantation characteristics and outcomes of all consecutive patients between the years 2003 and 2017 (n=51) diagnosed with primary refractory AML who underwent transplantation at the University of Cologne and the Tel Aviv Medical Center. Median age was 54 years and median follow up was 37 months. Median time to neutrophil and platelet engraftment was 13 (range, 8-19) and 13 (range, 7-30) days, respectively. None of the patients had primary graft failure. Incidences of grade 2-4 and grade 3-4 acute graft-v
-host disease (GvHD), overall and moderate-severe chronic GvHD were 50% (95%CI: 41-67%), 12% (95%CI: 3-25%), 61% (95%CI: 47-72%), and 42% (95%CI: 34-51%), respectively. Anti-thymocyte globulin administration was associated with lower incidence of acute GvHD (HR: 0.327;
=0.02). Non-relapse mortality at three months and three years were 6% and 16%, respectively. Relapse incidences were 6% and 29%, respectively. Overall survival rates at three months, three and five years were 90%, 61%, and 53%, respectively. Chronic GvHD disease was associated with a decreased mortality rate (HR: 0.397;
=0.045). We conclude that sequential therapy in patients with primary refractory acute myeloid leukemia is safe and provides a remarkable anti-leukemic effect with durable survival and should be considered for every patient with primary refractory disease.
Post-transplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that can arise after solid organ ...transplantation (SOT) and allogeneic hematopoietic transplantation (allo-HSCT).
In this multi-center retrospective study, we compare patient characteristics, therapies, and outcomes of PTLD after allo-HSCT and SOT. Twenty-five patients (15 after allo-HSCT and 10 after SOT) were identified who developed PTLD between 2008 and 2022.
Median age (57 years; range, 29-74 years) and baseline characteristics were comparable between the two groups (allo-HSCT vs SOT), but median onset of PTLD was markedly shorter after allo-HSCT (2 months vs. 99 months, P<0.001). Treatment regimens were heterogeneous, with reduction of immunosuppression in combination with rituximab being the most common first-line treatment strategy in both cohorts (allo-HSCT: 66%; SOT: 80%). The overall response rate was lower in the allo-HSCT (67%) as compared to the SOT group (100%). Consequently, the overall survival (OS) trended towards a worse outcome for the allo-HSCT group (1-year OS: 54% vs. 78%; P=0.58). We identified PTLD onset ≤150 days in the allo-HSCT (P=0.046) and ECOG >2 in the SOT group (P=0.03) as prognostic factors for lower OS.
PTLD cases present heterogeneously and pose unique challenges after both types of allogeneic transplantation.
Bone marrow mesenchymal stem cells (MSC) have potent immunosuppressive properties and have been advocated for therapeutic use in humans. The nature of their suppressive capacity is poorly understood ...but is said to be a primitive stem cell function. Demonstration that adult stromal cells such as fibroblasts (Fb) can modulate T cells would have important implications for immunoregulation and cellular therapy. In this report, we show that dermal Fb inhibit allogeneic T cell activation by autologously derived cutaneous APCs and other stimulators. Fb mediate suppression through soluble factors, but this is critically dependent on IFN-gamma from activated T cells. IFN-gamma induces IDO in Fb, and accelerated tryptophan metabolism is at least partly responsible for suppression of T cell proliferation. T cell suppression is reversible, and transient exposure to Fb during activation reprograms T cells, increasing IL-4 and IL-10 secretion upon restimulation. Increased Th2 polarization by stromal cells is associated with amelioration of pathological changes in a human model of graft-vs-host disease. Dermal Fb are highly clonogenic in vitro, suggesting that Fb-mediated immunosuppression is not due to outgrowth of rare MSC, although dermal Fb remain difficult to distinguish from MSC by phenotype or transdifferentiation capacity. These results suggest that immunosuppression is a general property of stromal cells and that dermal Fb may provide an alternative and accessible source of cellular therapy.
PDF
