Soluble trivalent engagers redirect cytolytic T cell activity toward tumor endothelial marker 1.

Tumor endothelial marker 1 (TEM1) is an emerging cancer target with a unique dual expression profile. First, TEM1 is expressed in the stroma and neo-vasculature of many human carcinomas but is largely absent from healthy adult tissues. Second, TEM1 is expressed by tumor cells of mesenchymal origin, notably sarcoma. Here, we present two fully human anti-TEM1 single-chain variable fragment (scFv) reagents, namely, 1C1m and 7G22, that recognize distinct regions of the extracellular domain and possess substantially different affinities. In contrast to other, well-described anti-TEM1 binders, these fragments confer cytolytic activity when expressed as 2 <sup>nd</sup> generation chimeric antigen receptors (CARs). Moreover, both molecules selectively redirect human T cell effector functions toward TEM1 <sup>+</sup> tumor cells when incorporated into experimental soluble bispecific trivalent engagers that we term TriloBiTEs (tBs). Furthermore, systemic delivery of 1C1m-tB prevents the establishment of Ewing sarcoma tumors in a xenograft model. Our observations confirm TEM1 as a promising target for cancer immunotherapy and illustrate the prospective translational potential of certain scFv-based reagents

A cell-based phenotypic library selection and screening approach for the de novo discovery of novel functional chimeric antigen receptors.

Anti-tumor therapies that seek to exploit and redirect the cytotoxic killing and effector potential of autologous or syngeneic T cells have shown extraordinary promise and efficacy in certain clinical settings. Such cells, when engineered to express synthetic chimeric antigen receptors (CARs) acquire novel targeting and activation properties which are governed and orchestrated by, typically, antibody fragments specific for a tumor antigen of interest. However, it is becoming increasingly apparent that not all antibodies are equal in this regard, with a growing appreciation that 'optimal' CAR performance requires a consideration of multiple structural and contextual parameters. Thus, antibodies raised by classical approaches and intended for other applications often perform poorly or not at all when repurposed as CARs. With this in mind, we have explored the potential of an in vitro phenotypic CAR library discovery approach that tightly associates antibody-driven bridging of tumor and effector T cells with an informative and functionally relevant CAR activation reporter signal. Critically, we demonstrate the utility of this enrichment methodology for 'real world' de novo discovery by isolating several novel anti-mesothelin CAR-active scFv candidates

Variceal bleeding: consensus meeting report from the Brazilian Society of Hepatology Hemorragia digestiva alta varicosa: relatório do 1º Consenso da Sociedade Brasileira de Hepatologia

In the last decades, several improvements in the management of variceal bleeding have resulted in a significant decrease in morbidity and mortality of patients with cirrhosis and bleeding varices. Progress in the multidisciplinary approach to these patients has led to a better management of this disease by critical care physicians, hepatologists, gastroenterologists, endoscopists, radiologists and surgeons. In this respect, the Brazilian Society of Hepatology has, recently, sponsored a consensus meeting in order to draw evidence-based recommendations on the management of these difficult-to-treat subjects. An organizing committee comprised of four people was elected by the Governing Board and was responsible to invite 27 researchers from distinct regions of the country to make a systematic review of the subject and to present topics related to variceal bleeding, including prevention, diagnosis, management and treatment, according to evidence-based medicine. After the meeting, all participants met together for discussion of the topics and the elaboration of the aforementioned recommendations. The organizing committee was responsible for writing the final document. The meeting was held at Salvador, May 6th, 2009 and the present manuscript is the summary of the systematic review that was presented during the meeting, organized in topics, followed by the recommendations of the Brazilian Society of Hepatology.<br>Vários avanços científicos obtidos nas últimas duas décadas foram incorporados no manejo da hemorragia digestiva alta varicosa, levando a uma redução significante da sua morbimortalidade, atribuída à abordagem multidisciplinar do sangramento varicoso por paramédicos, emergencistas, intensivistas, gastroenterologistas, hepatologistas, endoscopistas, radiologistas intervencionistas e cirurgiões. Recentemente, a Sociedade Brasileira de Hepatologia patrocinou uma reunião de consenso, visando o estabelecimento de recomendações nacionais, sobre o manejo da hemorragia digestiva alta varicosa, incluindo sua prevenção, diagnóstico e tratamento, de acordo com a melhor evidência científica disponível. A diretoria da Sociedade Brasileira de Hepatologia elegeu quatro membros para a comissão organizadora que, por sua vez, convidou 27 pesquisadores de diferentes regiões do país, para realizar uma revisão sistemática sobre tópicos relacionados ao manejo hemorragia digestiva alta varicosa. A reunião de consenso ocorreu em Salvador, BA, em 6 de março de 2009. Após o encontro, todos os participantes se reuniram para elaboração das recomendações, cuja redação ficou sob a responsabilidade da comissão organizadora. O presente artigo descreve as recomendações da Sociedade Brasileira de Hepatologia sobre o manejo do sangramento associado à hipertensão portal, divididas em módulos e precedidas por resumo das apresentações realizadas na reunião de consenso