Immunotherapy with CD25/CD71-allodepleted T cells to improve T-cell reconstitution after matched unrelated donor hematopoietic stem cell transplant: a randomized trial

BACKGROUND AND AIMS: Delayed immune reconstitution is a major challenge after matched unrelated donor (MUD) stem cell transplant (SCT). In this randomized phase 2 multi-center trial, Adoptive Immunotherapy with CD25/71 allodepleted donor T cells to improve immunity after unrelated donor stem cell transplant (NCT01827579), the authors tested whether allodepleted donor T cells (ADTs) can safely be used to improve immune reconstitution after alemtuzumab-based MUD SCT for hematological malignancies. METHODS: Patients received standard of care or up to three escalating doses of ADTs generated through CD25+/CD71+ immunomagnetic depletion. The primary endpoint of the study was circulating CD3+ T-cell count at 4 months post-SCT. Twenty-one patients were treated, 13 in the ADT arm and eight in the control arm. RESULTS: The authors observed a trend toward improved CD3+ T-cell count at 4 months in the ADT arm versus the control arm (230/µL versus 145/µL, P = 0.18), and three ADT patients achieved normal CD3+ T-cell count at 4 months (>700/µL). The rates of significant graft-versus-host disease (GVHD) were comparable in both cohorts, with grade ≥2 acute GVHD in seven of 13 and four of eight patients and chronic GVHD in three of 13 and three of eight patients in the ADT and control arms, respectively. CONCLUSIONS: These data suggest that adoptive transfer of ADTs is safe, but that in the MUD setting the benefit in terms of T-cell reconstitution is limited. This approach may be of more use in the context of more rigorous T-cell depletion

Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1,2,3,4,5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40–60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19− clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9,10,11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1,2,3,4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectivel

A New Crocodylian from the Late Maastrichtian of Spain: Implications for the Initial Radiation of Crocodyloids

The earliest crocodylians are known primarily from the Late Cretaceous of North America and Europe. The representatives of Gavialoidea and Alligatoroidea are known in the Late Cretaceous of both continents, yet the biogeographic origins of Crocodyloidea are poorly understood. Up to now, only one representative of this clade has been known from the Late Cretaceous, the basal crocodyloid Prodiplocynodon from the Maastrichtian of North America.The fossil studied is a skull collected from sandstones in the lower part of the Tremp Formation, in Chron C30n, dated at -67.6 to 65.5 Ma (late Maastrichtian), in Arén (Huesca, Spain). It is located in a continuous section that contains the K/P boundary, in which the dinosaur faunas closest to the K/P boundary in Europe have been described, including Arenysaurus ardevoli and Blasisaurus canudoi. Phylogenetic analysis places the new taxon, Arenysuchus gascabadiolorum, at the base of Crocodyloidea.The new taxon is the oldest crocodyloid representative in Eurasia. Crocodyloidea had previously only been known from the Palaeogene onwards in this part of Laurasia. Phylogenetically, Arenysuchus gascabadiolorum is situated at the base of the first radiation of crocodyloids that occurred in the late Maastrichtian, shedding light on this part of the cladogram. The presence of basal crocodyloids at the end of the Cretaceous both in North America and Europe provides new evidence of the faunal exchange via the Thulean Land Bridge during the Maastrichtian

Hadrosauroid dinosaurs from the Latest Cretaceous of the Iberian Peninsula

This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Vertebrate Paleontology on 2009, available online: https://doi.org/10.1671/039.029.0317XPS acknowledges the financial support provided by the Spanish Ministerio de Educacion y Ciencia (MEC) (Programa Ramon y Cajal; projects CGL2004-02338 and CGL2007-64061/BTE) the UPV/EHU (9/UPV 00121.310-15303/2003) and the Basque Government (CIC07/14-361). Research work of JIC and PCC was supported by the MEC and the ERDF (CGL 200403393, CGL2007-62469/BTE) and the Government of Aragon (Grupos Consolidados 2007, Department for Education and Culture). Research of JIR-O is supported by the Regional Ministry for Culture and Tourism of the Principality of Asturias (Protocolo CN-04-226). The manuscript was significantly improved thanks to the helpful reviews from P. Godefroit and F. Dalla Vecchia. Z. Herrera and I. Perez-Urresti (Univ. Zaragoza) prepared some of the photographs. A. Galobart (IPS, Sabadell) and A. Prieto-Morquez (Florida State University, Tallahassee) facilitated information to us.Pereda-Suberbiola, X.; Canudo, JI.; Company Rodríguez, J.; Cruzado-Caballero, P.; Ruiz-Omeñaca, JI. (2009). Hadrosauroid dinosaurs from the Latest Cretaceous of the Iberian Peninsula. Journal of Vertebrate Paleontology. 29(3):946-951. https://doi.org/10.1671/039.029.0317S946951293Averianov, A., & Archibald, J. D. (2005). Mammals from the mid-Cretaceous Khodzhakul Formation, Kyzylkum Desert, Uzbekistan. Cretaceous Research, 26(4), 593-608. doi:10.1016/j.cretres.2005.03.007Bolotsky, Y. L., & Godefroit, P. (2004). A new hadrosaurine dinosaur from the Late Cretaceous of Far Eastern Russia. Journal of Vertebrate Paleontology, 24(2), 351-365. doi:10.1671/1110CASANOVAS, M. L., PEREDA SUBERBIOLA, X., SANTAFE, J. V., & WEISHAMPEL, D. B. (1999). First lambeosaurine hadrosaurid from Europe: palaeobiogeographical implications. Geological Magazine, 136(2), 205-211. doi:10.1017/s0016756899002319Casanovas, M. L., Pereda Suberbiola, X., Santafé, J. V., & Weishampel, D. B. (1999). Geologie en Mijnbouw, 78(3/4), 345-356. doi:10.1023/a:1003859501941Company, J. 2004. 410 Vertebrados continentales del Cretácico superior (Campaniense-Maastrichtiense) de Valencia. Ph.D. dissertation, Universidad de Valencia, ValenciaEvans, D. C., & Reisz, R. R. (2007). Anatomy and Relationships ofLambeosaurus magnicristatus, a crested hadrosaurid dinosaur (Ornithischia) from the Dinosaur Park Formation, Alberta. Journal of Vertebrate Paleontology, 27(2), 373-393. doi:10.1671/0272-4634(2007)27[373:aarolm]2.0.co;2Gaete, R., Prieto-Márquez, A., Riera, V., Oms, O. and Galobart, A. 2007. “New discoveries of lambeosaurine hadrosaurids from the Tremp Basin (Maastrichtian, southern Pyrenees): description and stratigraphic setting; p.”. 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