The objective of this article is to assess the safety of intraspinal infusion of autologous bone marrow mononuclear cells (BMNCs) and, ultimately, to look for histopathological signs of cellular ...neurotrophism in amyotrophic lateral sclerosis (ALS) patients. We conducted an open single arm phase I trial. After 6 months observation, autologous BMNCs were infused into the posterior spinal cord funiculus. Safety was the primary endpoint and was defined as the absence of serious transplant-related adverse events. In addition, forced vital capacity (FVC), ALS-functional rating scale (ALS-FRS), Medical Research Council scale for assessment of muscle power (MRC), and Norris scales were assessed 6 and 3 months prior to the transplant and quarterly afterward for 1 year. Pathological studies were performed in case of death. Eleven patients were included. We did not observe any severe transplant-related adverse event, but there were 43 nonsevere events. Twenty-two (51%) resolved in ≤2 weeks and only four were still present at the end of follow-up. All were common terminology criteria for adverse events grade ≤2. No acceleration in the rate of decline of FVC, ALS-FRS, Norris, or MRC scales was observed. Four patients died on days 359, 378, 808, and 1,058 post-transplant for reasons unrelated to the procedure. Spinal cord pathological analysis showed a greater number of motoneurons in the treated segments compared with the untreated segments (4.2 ± 0.8 motoneurons per section mns per sect and 0.9 ± 0.3 mns per sect, respectively). In the treated segments, motoneurons were surrounded by CD90+ cells and did not show degenerative ubiquitin deposits. This clinical trial confirms not only the safety of intraspinal infusion of autologous BMNC in ALS patients but also provides evidence strongly suggesting their neurotrophic activity.
BACKGROUND: Products cryopreserved with dimethyl sulfoxide (DMSO) in stem cell transplant (SCT) often cause many adverse effects during their infusion (major cardiovascular events, dyspnea … even ...death). These are especially frequent in pediatric patients. We tested if a fully automated and closed wash procedure (Sepax S‐100, Biosafe) allowed us to maintain the absolute CD34+ cell number, cell viability, and engraftment potential, decreasing the untoward reactions.
STUDY DESIGN AND METHODS: Forty‐six washes of DMSO cryopreserved peripheral blood hematopoietic progenitor (HP) apheresis were studied. Blood aliquots were taken both after thawing and after washing to assess the total nucleated and CD34+ cell counts, as well as cell viability. The washed products were infused in 26 autologous SCTs (ASCTs). Results were compared with the 53 previous SCTs performed without DMSO removal.
RESULTS: After washing there were no significant differences between the pre‐ and postwashing CD34+ cell counts (p = 0.08) or viability (p = 0.68). No significant differences were observed between washed and nonwashed infusions in relation to the day of the neutrophil (p = 0.46) and platelet (p = 0.26) engraftment. One adverse event, abdominal pain, occurred during the washed cells infusions. When compared with the 14 untoward reactions that took place during the nonwashed HP infusions, significance was reached (p = 0.00043).
CONCLUSIONS: The automatic method described is effective in terms of CD34+ cell recovery and viability in ASCT. Moreover, Sepax decreased significantly the untoward reactions during the infusion.
The kinetics of SARS-CoV-2 reactive IgG antibodies after full vaccination and booster in allogeneic and autologous stem cell transplantation (allo-HSCT, ASCT) and chimeric antigen receptor T-cell ...therapy (CAR-T) are of utmost importance for estimating risk of infection. A prospective multicenter registry-based cohort study, conducted from December 2020 to July 2022 was used to analyze antibody waning over time, booster effect and the relationship of antibody response and breakthrough infection in 572 recipients (429 allo-HSCT, 121 ASCT and 22 CAR-T cell therapy). A significant decline in antibody titers was observed at 3 and 6 months after full vaccination in recipients without pre-vaccine SARS-CoV-2 infection, whereas recipients infected prior to vaccination showed higher and stable antibody titers over time. In poor responders, a booster dose was able to increase antibody titers in 83% of allo-HSCT and 58% of ASCT recipients but not in CART-T cell recipients 0% (p < 0.01). One-year cumulative incidence of breakthrough infection was 15%, similar among cell therapy procedures. Immunosuppressive drugs at the time of vaccination hazard ratio (HR) 1.81, p = 0.0028 and reduced intensity conditioning (HR 0.49, p = 0.011) were identified as the only conditions associated with different risk of breakthrough infection in allo-HSCT recipients. Antibody titers were associated with breakthrough infection and disease severity. No death was observed among the 72 breakthrough infections. Antibody level decay after the first two vaccine doses was common except in recipients with pre-vaccination SARS-CoV-2 infection. Poorly responding allo-HSCT recipients showed a response advantage with the booster as compared to ASCT and, especially, the null response found in CAR-T cell recipients. Antibody titers were positively correlated with the risk of breakthrough SARS-CoV-2 infection which was mainly driven by the immunosuppression status.
The long-term clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has been little explored. A prospective multicenter ...registry-based cohort study conducted from December 2020 to July 2022 by the Spanish Transplant and Cell Therapy group, was used to analyze the relationship of antibody response over time after full vaccination (at 3-6 weeks, 3, 6 and 12 months) (2 doses) and of booster doses with breakthrough SARS-CoV-2 infection in 1551 patients with hematological disorders. At a median follow-up of 388 days after complete immunization, 266 out of 1551 (17%) developed breakthrough SARS-CoV-2 infection at median of 86 days (range 7-391) after full vaccination. The cumulative incidence was 18% 95% confidence interval (C.I.), 16-20%. Multivariate analysis identified higher incidence in chronic lymphocytic leukemia patients (29%) and with the use of corticosteroids (24.5%), whereas female sex (15.5%) and more than 1 year after last therapy (14%) were associated with a lower incidence (p < 0.05 for all comparisons). Median antibody titers at different time points were significantly lower in breakthrough cases than in non-cases. A serological titer cut-off of 250 BAU/mL was predictive of breakthrough infection and its severity. SARS-CoV-2 infection-related mortality was encouragingly low (1.9%) in our series. Our study describes the incidence of and risk factors for COVID-19 breakthrough infections during the initial vaccination and booster doses in the 2021 to mid-2022 period. The level of antibody titers at any time after 2-dose vaccination is strongly linked with protection against both breakthrough infection and severe disease, even with the Omicron SARS-CoV-2 variant.
B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the ...high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial.
We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes.
At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% 95% confidence interval (CI), 89.5-100; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse.
Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.
•NEW treatment of 50 mg/L reduced 4 log spore/mL suspension of F. oxysporum.•Concentration of 75 mg/L or higher, destroyed all cells of F. oxysporum from 7.1 log spores/mL.•NEW pretreatments up to ...100 mg/L had a stimulating effect on the germination capacity in•cucumber seeds.•For tomato and lettuce seeds, a NEW pretreatment of 50 mg/L for 12-h increases its•germination capacity.•For cucumber and lettuce seeds soaked in germinators with substrate, 12-h NEW•pretreatments promote plan growth.
Seed germination is critical for seedling procedures, and new technologies are required to increase crop yields. Some substances are considered elicitors or stimulating agents because they promote seed germination as well as plant growth (like root and plumule length, and germination rate among others). Some of these, could be applied during plant growth, or in earlier phases before germination as seeds pretreatment. Neutral electrolyzed water (NEW) is a solution of oxidizing agents mainly studied for its antimicrobial power mainly applied to food pathogens, and in less reports to phytopathogens. The objective of this work is to evaluate the effect of NEW on germination and morphological parameters of tomato (Lycopersicon esculentum), cucumber (Cucumis sativus) and lettuce (Lactuca sativa L.) seeds as well as to evaluate the in vitro activity of NEW against F. oxysporum. Two experiments were carried out to determine the in vitro and in vivo effects of NEW in seed pretreatment and another in vitro experiment was also carried out to determine antifungal effect against F. oxysporum. NEW in vitro treatments at 50 mg/L decreased spore concentration greater than 4 log spores/mL. Germination parameters and morphological variables were analyzed after NEW pretreatments. For in vitro germination, NEW pretreatments up to 75 mg/L did not show effect on germination parameters however highest dose was slightly adverse (4% against water control). For in vivo germination, NEW pretreatment of 100 mg/L had a stimulating effect on the germination rate in cucumber seeds (100% FGP against 83% FGP for water control). For tomato seeds germination neither stimulate nor adverse effect was observed (same percentage as water control). For lettuce seeds germination an inhibitory effect for 12 and 24 h of exposure time was achieved (73% NEW treatment against 90% of water control). For tomato and lettuce seeds, the NEW pretreatment of 50 mg/L during 12 h increased its germination capacity.
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Alopecia areata is an autoimmune disease that produces non-scarring hair loss around the body. Gene variants of the cytotoxic T-lymphocyte antigen 4 (CTLA4) gene, a negative regulator of T-cell ...response, have been associated with a predisposition to autoimmune diseases in different populations; however, the involvement of these genetic variants in the development of AA is controversial.
The present study evaluated the potential association of two CTLA4 gene variants with alopecia areata in a Mexican population.
We genotyped +49AG (rs231775) and CT60 (rs3087243) variants in 50 AA patients and 100 healthy control participants through PCR-RFLP.
No statistical difference was observed for either of the gene variants regarding allele or genotype frequencies between AA patients and the controls when the parameters of family/personal history of autoimmune diseases or gender were considered (p>0.05). Study limitations: Small sample size of patients and the data were obtained from Northeast Mexico population.
The genetic variants rs231775 and rs3087243 of the CTLA4 gene are not a risk factor for the development of alopecia areata in the analyzed Mexican population.
This is a multicenter prospective observational study that included a large cohort (n = 397) of allogeneic (allo‐HSCT; (n = 311) and autologous (ASCT) hematopoietic stem cell transplant (n = 86) ...recipients who were monitored for antibody detection within 3–6 weeks after complete severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccination from February 1, 2021, to July 20, 2021. Most patients (n = 387, 97.4%) received mRNA‐based vaccines. Most of the recipients (93%) were vaccinated more than 1 year after transplant. Detectable SARS‐CoV‐2‐reactive antibodies were observed in 242 (78%) of allo‐HSCT and in 73 (85%) of ASCT recipients. Multivariate analysis in allo‐HSCT recipients identified lymphopenia < 1 × 109/ml (odds ratio OR 0.33, 95% confidence interval 95% CI 0.16–0.69, p = .003), active graft versus host disease (GvHD; OR 0.51, 95% CI 0.27–0.98, p = .04) and vaccination within the first year of transplant (OR 0.3, 95% CI 0.15–0.9, p = .04) associated with lower antibody detection whereas. In ASCT, non‐Hodgkin's lymphoma (NHL; OR 0.09, 95% CI 0.02–0.44, p = .003) and active corticosteroid therapy (OR 0.2, 95% CI 0.02–0.87, p = .03) were associated with lower detection rate. We report an encouraging rate of SARS‐CoV‐2‐reactive antibodies detection in these severe immunocompromised patients. Lymphopenia, GvHD, the timing of vaccine, and NHL and corticosteroids therapy should be considered in allo‐HSCT and ASCT, respectively, to identify candidates for SARS‐CoV‐2 antibodies monitoring.
The clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has not yet been established.
A prospective multicenter ...registry-based cohort study conducted from December 2020 to December 2021 by the Spanish transplant and cell therapy group was used to analyze the relationship of antibody response at 3-6 weeks after full vaccination (2 doses) with breakthrough SARS-CoV-2 infection in 1394 patients with hematological disorders.
At a median follow-up of 165 days after complete immunization, 37 out of 1394 (2.6%) developed breakthrough SARS-CoV-2 infection at median of 77 days (range 7-195) after full vaccination. The incidence rate was 6.39 per 100 persons-year. Most patients were asymptomatic (19/37, 51.4%), whereas only 19% developed pneumonia. The mortality rate was 8%. Lack of detectable antibodies at 3-6 weeks after full vaccination was the only variable associated with breakthrough infection in multivariate logistic regression analysis (Odds Ratio 2.35, 95% confidence interval 1.2-4.6, p = 0.012). Median antibody titers were lower in cases than in non-cases 1.83 binding antibody units (BAU)/mL (range 0-4854.93) vs 730.81 BAU/mL (range 0-56,800), respectively (p = 0.007). We identified 250 BAU/mL as a cutoff above which incidence and severity of the infection were significantly lower.
Our study highlights the benefit of developing an antibody response in these highly immunosuppressed patients. Level of antibody titers at 3 to 6 weeks after 2-dose vaccination links with protection against both breakthrough infection and severe disease for non-Omicron SARS-CoV-2 variants.
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