Targeting HER2/neu with a fully human IgE to harness the allergic reaction against cancer cells

Breast and ovarian cancer are two of the leading causes of cancer deaths among women in the United States. Overexpression of the HER2/neu oncoprotein has been reported in patients affected with breast and ovarian cancers, and is associated with poor prognosis. To develop a novel targeted therapy for HER2/neu expressing tumors, we have constructed a fully human IgE with the variable regions of the scFv C6MH3-B1 specific for HER2/neu. This antibody was expressed in murine myeloma cells and was properly assembled and secreted. The Fc region of this antibody triggers in vitro degranulation of rat basophilic cells expressing human FcεRI (RBL SX-38) in the presence of murine mammary carcinoma cells that express human HER2/neu (D2F2/E2), but not the shed (soluble) antigen (ECDHER2) alone. This IgE is also capable of inducing passive cutaneous anaphylaxis in a human FcεRIα transgenic mouse model, in the presence of a cross-linking antibody, but not in the presence of soluble ECDHER2. Additionally, IgE enhances antigen presentation in human dendritic cells and facilitates cross-priming, suggesting that the antibody is able to stimulate a secondary T-cell anti-tumor response. Furthermore, we show that this IgE significantly prolongs survival of human FcεRIα transgenic mice bearing D2F2/E2 tumors. We also report that the anti-HER2/neu IgE is well tolerated in a preliminary study conducted in Macaca fascicularis (cynomolgus) monkeys. In summary, our results suggest that this IgE should be further explored as a potential therapeutic against HER2/neu overexpressing tumors, such as breast and ovarian cancers.Fil: Daniels, Tracy R.. University of California at Los Angeles; Estados UnidosFil: Leuchter, Richard K.. University of California at Los Angeles; Estados UnidosFil: Quintero, Rafaela. University of California; Estados UnidosFil: Helguera, Gustavo Fernando. University of California at Los Angeles; Estados Unidos. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rodríguez, José A.. University of California at Los Angeles; Estados UnidosFil: Martínez Maza, Otoniel. University of California at Los Angeles; Estados UnidosFil: Schultes, Birgit C.. Advanced Immune Therapeutics, Inc.; Estados Unidos. Momenta Pharmaceuticals, Inc.; Estados UnidosFil: Nicodemus, Christopher F.. Advanced Immune Therapeutics, Inc.; Estados UnidosFil: Penichet, Manuel L.. University of California at Los Angeles; Estados Unido

Preparing accessible and understandable clinical research participant information leaflets and consent forms: a set of guidelines from an expert consensus conference

Background In line with Good Clinical Practice and the Declaration of Helsinki, it is the investigator’s responsibility to ensure that research participants are sufficiently informed, to enable the provision of informed consent. The Participant Information Leaflet/Informed Consent Form is key to facilitating this communication process. Although studies have indicated that clinical research Participant Information Leaflets/Informed Consent Forms are not optimal in terms of accessibility, there is little or no specific guidance available. The aim of this research was to propose and agree a set of guidelines for academic researchers and sponsors for preparing accessible and understandable Participant Information Leaflets/Informed Consent Forms. Methods A literature review identified guidance for the preparation of patient-facing documents. Following critical appraisal, key recommendations were extracted and a set of recommendations which can be applied to clinical research Participant Information Leaflets/Informed Consent Forms were prepared. These recommendations were evaluated and amended by an Expert Consensus Conference consisting of a group of key stakeholders. The stakeholders included members of a Research Ethics Committee (both lay and expert), a patient advocate, experienced clinical researchers, a plain English editor and a Data Protection Officer. Consensus was reached regarding a final set of recommendations. Results 44 recommendations were agreed upon and grouped into five categories: Layout, Formatting, Content, Language and Confirming Readability. These recommendations aimed to maximize accessibility for lay participants, including readers with dyslexia, literacy or numeracy challenges, thereby improving the quality of the consent process. Conclusions More empirical research is needed to further improve the informed consent process for research participants. However, these recommendations are informed by the current literature and have been ratified by expert stakeholders. It is hoped that these recommendations will help investigators and sponsors to consistently and efficiently produce more accessible clinical research Participant Information Leaflets/Informed Consent Forms

Leading Up in the Scholarship of Teaching and Learning

Scholarship of teaching and learning (SoTL) scholars, including those who are not in formal positions of leadership, are uniquely positioned to engage in leadership activities that can grow the field, influence their colleagues, and effect change in their local contexts as well as in institutional, disciplinary, and the broader Canadian contexts. Drawing upon the existing SoTL literature and our own diverse experiences, we propose a framework that describes institutional contexts in terms of local SoTL activity (microcultures) and administrative support (macro-level) and use it to describe the many ways that SoTL scholars can and do “lead up” to effect change depending on their own context. We conclude by inviting scholars to consider, reflect upon, and experiment with their leadership activities, not only for their own professional growth but also to contribute to the literature in this area. Les professeurs qui font des recherches dans le domaine de l’avancement des connaissances en enseignement et en apprentissage (ACEA), y compris ceux qui n’occupent pas un poste de leadership formel, occupent une position unique pour s’engager dans des activités de leadership qui peuvent faire avancer le domaine, influencer leurs collègues et effectuer des changements dans leurs contextes locaux ainsi que dans les contextes plus vastes de leur établissement, de leur discipline et du contexte canadien en général. En nous appuyant sur la documentation déjà publiée en ACEA et sur nos diverses expériences personnelles, nous proposons un cadre qui décrit les contextes institutionnels en termes d’activités d’ACEA locales (micro-cultures) et de soutien administratif (niveau macro) que nous utilisons pour décrire les diverses manières dont les chercheurs en ACEA peuvent en arriver à effectuer des changements selon leur propre contexte. En conclusion, nous invitons les chercheurs à prendre en considération leurs activités de leadership, à y réfléchir et à faire des expériences, non seulement pour leur propre croissance professionnelle mais également pour contribuer à la documentation dans ce domaine