CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies

CAR T cells targeting CD19 provide promising options for treatment of B cell malignancies. However, tumor relapse from antigen loss can limit efficacy. We developed humanized, second-generation CAR T cells against another B cell–specific marker, B cell activating factor receptor (BAFF-R), which demonstrated cytotoxicity against human lymphoma and acute lymphoblastic leukemia (ALL) lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day preestablished tumor xenografts after a single treatment and retained efficacy against xenografts deficient in CD19 expression, including CD19-negative variants within a background of CD19-positive lymphoma cells. Four relapsed, primary ALLs with CD19 antigen loss obtained after CD19-directed therapy retained BAFF-R expression and activated BAFF-R-CAR, but not CD19-CAR, T cells. BAFF-R-CAR, but not CD19-CAR, T cells also demonstrated antitumor effects against an additional CD19 antigen loss primary patient–derived xenograft (PDX) in vivo. BAFF-R is amenable to CAR T cell therapy, and its targeting may prevent emergence of CD19 antigen loss variants

Activité anti-hyperglycémique et antiradicalaire des extraits des fruits de Raphia gentiliana De Wild. (Arecaceae)

Ce travail s’inscrit dans le cadre de la valorisation des extraits des tanins du fruit de Raphia gentiliana De wild, une plante médicinale utilisée comme hypoglycémiant par la population en République Démocratique Congo. L’étude est réalisée in vivo à partir d’un modèle animal constitué de 50 souris NMRI, chez qui on a provoqué une hyperglycémie temporaire par administration d’une solution de glucose (200 mg /ml). La réduction du pourcentage de glycémie des souris est mesurée deux heures après administration des extraits du fruit (0,2 g/kg) de R. gentiliana (extraits de tanins et extraits totaux aqueux). Les valeurs de glycémie obtenues sont comparées avec un contrôle positif (glibenclamid). Les résultats obtenus montrent que l’extrait aqueux donne la valeur la plus élevée de réduction de la valeur de glycémie par rapport au contrôle négatif soit de 52,6%. Une valeur comparable à celle du contrôle positif (52,5%). Les extraits des tanins dans l’étherdiéthylique (EED), l’acétate d’éthyle (EAE) et le n-butanol/butanone (EBB) indiquent respectivement un pourcentage de réduction de glycémie de 51,1%, 48,5% et 7,5%. La méthode de mesure de l’activité antiradicalaire est basée sur la détermination du pourcentage de réduction du radical DPPH en présence de l’extrait. Les propriétés antiradicalaires ont été mises en évidence par la mesure de la concentration efficace 50 (CE50) et le calcul de l’indice de l’efficacité antiradicalaire (EAR). Les résultats obtenus donnent les valeurs de CE50 et EAR suivantes pour les différents extraits : Extrait aqueux (EAQ) : 72 mgextraits/mgDPPH et 1,50 10-3 ; EAE : 60 mgextraits/mgDPPH et 1,67 10-3 ; EBB : 19 mgextraits/mgDPPH et 12,00 10-3. Il n’existe pas une corrélation directe entre l’activité antihyperglycémique et l’activité antiradicalaire.Mots clés : Raphia gentiliana, activité antioxydante, activité anti hyperglycémique, tanins

A randomised controlled trial of 3 versus 5 days artemether-lumefantrine regimen for uncomplicated Plasmodium falciparum treatment in pregnancy in Africa

Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased. We assessed the efficacy, tolerability and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine compared to the standard 3-day treatment in 48 pregnant women and 48 non-pregnant women with uncomplicated falciparum malaria in an open-label, randomized clinical trial. Babies were assessed at birth, 1, 3, 6 and 12 months. Nonlinear mixed-effects modelling was used to characterise the plasma concentration-time profiles of artemether and lumefantrine and their metabolites. Both regimens were highly efficacious (100% PCR-corrected cure rates) and well tolerated. Babies followed up to 1 year had normal development. Parasite clearance half-lives were longer in pregnant women (median [range]: 3.30 [1.39-7.83] hours) compared to non-pregnant women (2.43 [1.05-6.00] hours), p=0.005. Pregnant women had lower exposures to artemether and dihydroartemisinin compared to non-pregnant women, resulting in 1.2% decreased exposure for each additional week of gestational age. By term, these exposures were reduced by 48% compared to non-pregnant patients. The overall exposure to lumefantrine was improved with the extended regimen, with no significant differences in exposures to lumefantrine or desbutyl-lumefantrine between pregnant and non-pregnant women. The extended artemether-lumefantrine regimen was well tolerated and safe and increased the overall antimalarial drug exposure, and so could be a promising treatment option in pregnancy in areas with lower malaria transmission and/or emerging drug resistance (http://www.clinicalTrials.gov/;NCT01916954)

A randomised controlled trial of 3 versus 5 days artemether-lumefantrine regimen for uncomplicated Plasmodium falciparum treatment in pregnancy in Africa

Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased. We assessed the efficacy, tolerability and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine compared to the standard 3-day treatment in 48 pregnant women and 48 non-pregnant women with uncomplicated falciparum malaria in an open-label, randomized clinical trial. Babies were assessed at birth, 1, 3, 6 and 12 months. Nonlinear mixed-effects modelling was used to characterise the plasma concentration-time profiles of artemether and lumefantrine and their metabolites. Both regimens were highly efficacious (100% PCR-corrected cure rates) and well tolerated. Babies followed up to 1 year had normal development. Parasite clearance half-lives were longer in pregnant women (median [range]: 3.30 [1.39-7.83] hours) compared to non-pregnant women (2.43 [1.05-6.00] hours), p=0.005. Pregnant women had lower exposures to artemether and dihydroartemisinin compared to non-pregnant women, resulting in 1.2% decreased exposure for each additional week of gestational age. By term, these exposures were reduced by 48% compared to non-pregnant patients. The overall exposure to lumefantrine was improved with the extended regimen, with no significant differences in exposures to lumefantrine or desbutyl-lumefantrine between pregnant and non-pregnant women. The extended artemether-lumefantrine regimen was well tolerated and safe and increased the overall antimalarial drug exposure, and so could be a promising treatment option in pregnancy in areas with lower malaria transmission and/or emerging drug resistance (http://www.clinicalTrials.gov/;NCT01916954)

Pharmacokinetic study of rectal artesunate in children with severe malaria in Africa

When severe malaria is suspected in children, WHO recommends pre-treatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, cross-over clinical trial in 83 Congolese children with severe falciparum malaria, to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg) followed 12 hours later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at eleven fixed intervals, following 0- and 12-hour drug administrations. Clinical, laboratory and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large inter-individual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients however, reached previously suggested in vivo IC50 (98.7%) and IC90 (92.5%) values of combined concentrations of artesunate and dihydroartemisinin between 15 to 30 minutes after drug administration. The median (IQR) time above IC50 and IC90 was 5.68 hours (2.90-6.08) and 2.74 hours (1.52-3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7-54.5) for artesunate and 19.8% (10.3-35.3) for dihydroartemisinin. The initial 12-hour parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR) 84.3% (50.0-95.4) vs. 69.2% (45.7-93.6), respectively (p=0.49). Despite large inter-individual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe falciparum malaria, while they are transferred to a facility where parenteral artesunate is available.(www.clinicalTrials.gov : NCT02492178