Development of lentiviral vectors (LVs) in the field of immunotherapy and immune regeneration will strongly rely on biosafety of the gene transfer. We demonstrated previously the feasibility of ex ...vivo genetic programming of mouse bone marrow precursors with LVs encoding granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), which induced autonomous differentiation of long-lived dendritic cells (DCs), referred to as self-differentiated myeloid-derived antigen-presenting-cells reactive against tumors (SMART-DCs). Here, LV biosafety was enhanced by using a DC-restricted and physiological promoter, the major histocompatibility complex (MHC) II promoter, and including co-expression of the herpes simplex virus-thymidine kinase (sr39HSV-TK) conditional suicide gene. Tricistronic vectors co-expressing sr39HSV-TK, GM-CSF and IL-4 transcriptionally regulated by the MHCII promoter or the ubiquitous cytomegalovirus (CMV) promoter were compared. Despite the different gene transfer effects, such as the kinetics, levels of transgene expression and persistency of integrated vector copies, both vectors induced highly viable SMART-DCs, which persisted for at least 70 days in vivo and could be ablated with the pro-drug Ganciclovir (GCV). SMART-DCs co-expressing the tyrosine-related protein 2 melanoma antigen administered subcutaneously generated antigen-specific, anti-melanoma protective and therapeutic responses in the mouse B16 melanoma model. GCV administration after immunotherapy did not abrogate DC vaccination efficacy. This demonstrates proof-of-principle of genetically programmed DCs that can be ablated pharmacologically.
To analyze the outcome of solid organ transplantation (SOT) in patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT), a questionnaire survey was carried out within 107 ...European Group of Blood and Marrow Transplantation centers. This study covered HSCT between 1984 and 2007 in Europe. Forty‐five SOT in 40 patients were reported. Fifteen liver, 15 renal, 13 lung, 1 heart and 1 skin transplantations were performed in 28 centers. Overall survival (OS) of patients after SOT was 78% at 5 years (95% confidence interval CI, 64% to 92%). OS at 5 years was 100% for renal, 71% (95% CI, 46% to 96%) for liver and 63% (95% CI, 23% to 100%) for lung transplant recipients. The 2‐year‐incidence of SOT failure was 20% (95% CI, 4% to 36%) in patients with graft‐versus‐host disease (GvHD) and 7% (95% CI, 0% to 21%) in patients without GvHD before SOT. The relapse incidence for underlying malignant diseases was 4% at 5 years (95% CI, 0% to 12%). In summary, this study shows that selected patients receiving SOT after HSCT have a remarkably good overall and organ survival. These data indicate that SOT should be considered in selected patients with single organ failure after HSCT.
Selected patients receiving organ transplants after hematopoietic stem cell transplantation have good patient and organ survival.
Purpose
To evaluate the impact of bone metastasis (BM) onset toward prognosis in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib.
Methods
mRCC patients with BM and sunitinib as ...first targeted therapy between May 2005 and December 2012 were retrospectively analyzed. Patients with synchronous (s) BM or metachronous (m) BM were compared with regard to treatment and outcome time to clinical progression (TTcP), overall survival (OS), skeletal-related events (SRE). Descriptive statistics, Kaplan–Meier estimation of TTcP and OS, Cox regression analyses, and a landmark analysis were administered.
Results
BM was identified in 127 mRCC patients; thereof, 82 sunitinib-treated patients were analyzed sBM
n
= 57 (69.5 %), mBM
n
= 25 (30.5 %). Higher tumor grading (
p
= 0.029), male predominance (
p
= 0.02), and less second-line therapy (
p
= 0.001) were detected in sBM compared to mBM. SRE remained similar between subgroups (
p
= 0.462). TTcP during sunitinib was similar median sBM 8.1 (95 % CI 3.9–12.3) vs. mBM 8.7 (95 % CI 2.7–14.8) months,
p
= 0.903. OS remained significantly inferior in sBM patients compared to mBM median sBM 21.1 (95 % CI 16–26.2) months vs. mBM 38.5 (95 % CI 15–62) months,
p
= 0.001, which was confirmed by landmark analyses at 1.5, 3, 6, 9, and 12 months. However, OS after occurrence of BM was similar in both groups median sBM 24.2 (95 % CI 17.3–31.1) months vs. mBM 17.2 (95 % CI 8.4–26) months,
p
= 0.519.
Conclusions
mBM is associated with an improved OS compared to sBM in mRCC with sunitinib treatment, despite similar efficacy of sunitinib treatment in both groups of patients.
Background: Patients with follicular (FL) or mantle cell lymphoma (MCL) are incurable with conventional therapy. We investigated the safety and efficacy of rituximab consolidation after autologous ...stem cell transplantation (ASCT) in order to prevent relapse by clearance of minimal residual disease (MRD). Methods: Rituximab was given ∼8 weeks after CD34+ cell enriched ASCT at 375 mg/m2, weekly for 4 weeks. Monitoring of MRD was performed by repetitive PCR analyses. Results: Thirty-one patients were included; one died early after ASCT before rituximab administration. Thirty patients (20 FL, 10 MCL) were evaluable after rituximab consolidation, and 27 of these were assessable for MRD detection. Rituximab consolidation post-ASCT was safe, the most common toxicity being infection. At a median follow-up of 42 months (range 13–96) after ASCT, 25 patients were censored with an actuarial event-free survival (EFS) of 81% at 4 and 5 years. Four patients (two FL, two MCL) relapsed, and one additional MCL patient died unexpectedly in complete remission. PCR-negativity was observed in 22% of the patients before ASCT, 53% post-ASCT (P=0.0547), 72% after rituximab (P=0.0018) and 100% at 6 months post-transplant (P < 0.001). Conclusions: One single course of rituximab consolidation given after ASCT is safe, may help to eliminate MRD and may translate into improved EFS in both FL and MCL patients.
Bovine viral diarrhoea (BVD) is an endemic disease of cattle that causes substantial losses to both beef and dairy production worldwide. The goal of this study was to estimate the prevalence of ...active BVD virus (BVDV) infection in beef suckler herds in Scotland. Information was collected from 301 herds using a stratified random sampling design based on agricultural census data. Herds were classified as with and without active infection based on the within-herd BVDV seroprevalence in young stock using Bayesian finite mixture modelling. This method accounted for within- and between-herd variability and allowed for classification error by the diagnostic tests. The observed sample data enabled the discrimination of three distinct seroprevalence cohorts. The results provided evidence of active BVDV infection in 16% of herds and no evidence of recent exposure in approximately two thirds of herds. The epidemiological significance of the further 16% of herds containing young stock with a median BVDV seroprevalence of 26.3–38.5% remains unclear. The fact that a large percentage of herds did not show evidence of recent infection is encouraging from an animal health and welfare perspective and the study provides a model for the further exploration of strategies aimed at BVD control at national level.
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