Search

Background: UCART19 is an "off-the-shelf" genome-edited anti-CD19 chimeric antigen receptor (CAR)-T cell product, manufactured from unrelated healthy donor cells., Methods: UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities, and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology., Results: Responder patients (12/25) had higher UCART19 expansion ( C max ) and exposure (AUCT last ) than nonresponders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR + T cells did not exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected IL7 and UCART19 kinetics, while negatively correlating with host T lymphocyte AUC 0-28 ., Conclusions: UCART19 expansion is a driver of response in adult patients with R/R B-ALL. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection., Significance: First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population., Competing Interests: S. Dupouy reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. I. Marchiq reports other from Allogene Therapeutics during the conduct of the study; and I. Marchiq is an employee of Servier. T. Derippe reports grants from Servier during the conduct of the study; grants from Servier outside the submitted work. M. Almena-Carrasco reports personal fees from Servier Laboratoires and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier Laboratoires outside the submitted work. S. Fouliard reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. J. Geronimi reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. C. Graham reports grants from Servier during the conduct of the study. N. Jain reports grants, personal fees, and non-financial support from Servier during the conduct of the study; grants, personal fees, and non-financial support from Cellectis, Precision Biosciences, Abbvie, Genentech, Loxo Oncology, Fate Therapeutics; grants from Takeda outside the submitted work. M.V. Maus reports other from 2Seventy Bio outside the submitted work; in addition, M.V. Maus has a patent to Patents in CAR T cells for multiple indications pending; and M.V. Maus is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital (some licensed to Promab) and University of Pennsylvania (some licensed to Novartis). M.V. Maus holds Equity in 2SeventyBio, Century Therapeutics, Neximmune, Oncternal, and TCR2 and has served as a consultant for multiple companies involved in cell therapies; board of directors: 2Seventy Bio; M.V. Maus is a consultant for: Adaptimmune, Agenus, Allogene, Arcellx, Astellas, AstraZeneca, Atara, Bayer, BMS, Cabaletta Bio (SAB), Cellectis (SAB), CRISPR therapeutics, Genocea, In8bio (SAB), Intellia, GSK, Kite Pharma, Micromedicine/BendBio, Neximmune, Novartis, Oncternal, Sanofi, TCR2 (SAB), Tmunity, and WindMIL (SAB); M.V. Maus has had Grant/Research support : CRISPR therapeutics, Kite Pharma, Servier, Novartis; speaker's bureau: none. M. Mohty reports grants and personal fees from Jazz, Janssen, Sanofi; personal fees from Amgen, Takeda, Pfizer, Adaptive, Novartis, Astellas, GSK, Oncopeptides, and BMS outside the submitted work. N. Boissel reports personal fees from SERVIER during the conduct of the study; grants and personal fees from AMGEN; personal fees from Pfizer, Gilead, and Novartis outside the submitted work. T. Teshima reports grants from Sanofi, Chugai, Astellas, Teijin Pharma, Fuji Pharma, Nippon Shinyaku; personal fees from Merck Sharp & Dohme, Pfizer, Bristol-Myers Squibb; grants and personal fees from Kyowa Kirin; non-financial support from Janssen; grants, personal fees, and non-financial support from Novartis, and personal fees from Takeda outside the submitted work. K. Kato reports grants from Kyowa-Kirin, Novartis, Chugai, Takeda, AbbVie, Eisai, Janssen, Bristol-Myers Squibb, Ono, and Daiichi Sankyo during the conduct of the study. R. Benjamin reports grants from Servier and Allogene during the conduct of the study. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Chimeric antigen receptor (CAR)-T cell therapies have shown tremendous results against various hematologic cancers. Prior to cell infusion, a host preconditioning regimen is required to achieve lymphodepletion and improve CAR-T cell pharmacokinetic exposure, leading to greater chances of therapeutic success. To better understand and quantify the impact of the preconditioning regimen, we built a population-based mechanistic pharmacokinetic-pharmacodynamic model describing the complex interplay between lymphodepletion, host immune system, homeostatic cytokines, and pharmacokinetics of UCART19, an allogeneic product developed against CD19 + B cells. Data were collected from a phase I clinical trial in adult relapsed/refractory B-cell acute lymphoblastic leukemia and revealed three different UCART19 temporal patterns: (i) expansion and persistence, (ii) transient expansion with subsequent rapid decline, and (iii) absence of observed expansion. On the basis of translational assumptions, the final model was able to capture this variability through the incorporation of IL-7 kinetics, which are thought to be increased owing to lymphodepletion, and through an elimination of UCART19 by host T cells, which is specific to the allogeneic context. Simulations from the final model recapitulated UCART19 expansion rates in the clinical trial, confirmed the need for alemtuzumab to observe UCART19 expansion (along with fludarabine cyclophosphamide), quantified the importance of allogeneic elimination, and suggested a high impact of multipotent memory T-cell subpopulations on UCART19 expansion and persistence. In addition to supporting the role of host cytokines and lymphocytes in CAR-T cell therapy, such a model could help optimizing the preconditioning regimens in future clinical trials., Significance: A mathematical mechanistic pharmacokinetic/pharmacodynamic model supports and captures quantitatively the beneficial impact of lymphodepleting patients before the infusion of an allogeneic CAR-T cell product. Mediation through IL-7 increase and host T lymphocytes decrease is underlined, and the model can be further used to optimize CAR-T cell therapies lymphodepletion regimen., Competing Interests: T. Derippe reports grants from Servier during the conduct of the study; grants from Servier outside the submitted work. S. Fouliard reports personal fees from Servier during the conduct of the study. I. Marchiq reports other from Allogene Therapeutics during the conduct of the study; and I. Marchiq is an employee of Servier. S. Dupouy reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. M. Almena-Carrasco reports personal fees from Institut de Rechercher International Servier outside the submitted work. J. Geronimi reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. D.E. Mager reports grants from Servier during the conduct of the study. No disclosures were reported by the other author., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Background: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, which is associated with features of metabolic syndrome. NAFLD may progress in a subset of patients into nonalcoholic steatohepatitis (NASH) with liver injury resulting ultimately in cirrhosis and potentially hepatocellular carcinoma. Today, there is no approved treatment for NASH due to, at least in part, the lack of preclinical models recapitulating features of human disease. Here, we report the development of a dietary model of NASH in the Göttingen minipig., Methods: First, we performed a longitudinal characterization of diet-induced NASH and fibrosis using biochemical, histological, and transcriptional analyses. We then evaluated the pharmacological response to Obeticholic acid (OCA) treatment for 8 weeks at 2.5mg/kg/d, a dose matching its active clinical exposure., Results: Serial histological examinations revealed a rapid installation of NASH driven by massive steatosis and inflammation, including evidence of ballooning. Furthermore, we found the progressive development of both perisinusoidal and portal fibrosis reaching fibrotic septa after 6 months of diet. Histological changes were mechanistically supported by well-defined gene signatures identified by RNA Seq analysis. While treatment with OCA was well tolerated throughout the study, it did not improve liver dysfunction nor NASH progression. By contrast, OCA treatment resulted in a significant reduction in diet-induced fibrosis in this model., Conclusions: These results, taken together, indicate that the diet-induced NASH in the Göttingen minipig recapitulates most of the features of human NASH and may be a model with improved translational value to prioritize drug candidates toward clinical development., (© 2021 The Authors.)

Introduction: The aim of this study was to evaluate episiotomy technique, in particular suture angles, and any correlation between suture angle and severe perineal tears., Material and Methods: An observational questionnaire-based study was conducted between 01 August 2015 and 30 April 2016 among accoucheurs performing episiotomies in a French maternity unit with facilities for high-risk pregnancies. For each patient included, accoucheurs were asked to measure the episiotomy suture angle, and to record the angle at which they thought they had cut, the length of the episiotomy, its distance from the anus, and whether the woman sustained a sphincter injury., Results: The centre's episiotomy rate during the study period was 15%. We analyzed the characteristics of episiotomies performed on 89 women (68 by doctors and 21 by midwives). Only 43% of suture angles were between 45° and 60° (45.6% of those performed by doctors vs 38.1% by midwives, p=0.8623), whereas 91% of accoucheurs thought they had cut within the correct range. Doctors made longer incisions than midwives (4 [4.2-5.0] vs 3 [2.5-3.5] cm, p=0.0006). Only 40.5% of accoucheurs correctly estimated the incision angle. Twelve (13.64%) of the 88 women sustained a third-degree perineal tear. The risk of sphincter injury was higher with suture angles <45° (odds ratio 5.46 [1.11-26.75], p=0.037). After multivariate analysis, this result was no longer significant (p=0.079)., Conclusion: It appears that many accoucheurs have difficulty estimating episiotomy incision angles correctly and that education and training in this domain requires improvement., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)