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Abstract 3746: Plasma membrane spanning and linker-domains from tumor necrosis factor receptor superfamily (TNFRSF) proteins provide novel functionality to chimeric antigen receptors (CARs) expressed in human T cells
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Chimeric antigen receptor T cells redirected to the B cell antigen CD19 (CAR19) have shown efficacy in the treatment of B-lineage acute lymphocytic leukemia, and are being evaluated in other hematologic malignancies as well. The prevalent configuration of CAR19 for clinical application is comprised of the extracellular single chain targeting domain (scFv) derived from the FMC63 antibody, a CD8 linker and transmembrane domain, a CD137 signaling domain, and a CD3-zeta signaling domain. Transmembrane domains from other immunologically-active proteins, including CD3, CD28, or CD4, and spacer domains from IgG have been employed as structural components of CARs as well. The relationship between the composition of the CAR linker and transmembrane domain and CAR T function is, however, poorly understood. We hypothesized that CAR transmembrane and linker domains derived from proteins of the tumor necrosis factor receptor superfamily (TNFRSF), whose expression is associated with normal T cell functions, may optimize the anti-tumor activity of CAR19. Therefore, primary human T cells were transduced with lentiviral expression vectors (LV) expressing new combinations of linker and transmembrane sequences encoded by various TNFRSF members. Specifically, the linker:transmembrane domain combinations were: CD8:CD4, CD8:TNFRSF19, TNFRSF19:TNFRSF19, truncated TNFRSF19:TNFRSF19, TNFRSF9:TNFRSF9 and TNFRSF16:TNFRSF16.
We found that CAR T cells comprised of transmembrane domains derived from either TNFRSF19 or TNFRSF9 were superior to the CD8 transmembrane CAR 19 in tumor killing, and in the induction of IFN gamma, TNF alpha, IL-2, and GM-CSF cytokine secretion in vitro, upon co-culture with leukemia cell line targets. Moreover, TNFRSF19-expressing CAR19 T cells were superior to the CD8 transmembrane CAR19 in the elimination of engrafted Raji cells (a Burkitt’s lymphoma line) in an NSG leukemia mouse model. On the other hand, the transmembrane domain derived from TNFRSF16/LNGFR, a low affinity neurotrophin receptor, created a CAR19 construct that had no functional activity either in vitro or in vivo, despite high levels of surface CAR expression in human T cells.
In conclusion, the magnitude of CAR T response can be enhanced by the use of novel linker and transmembrane domains derived from TNFRSF19 and TNFRSF9. Thus, the transmembrane domain can play a determining role in CAR T function beyond a direct topographical connection between the extracellular and the intracellular domains of the chimeric protein. Studies are underway to elucidate the mechanistic role of TNFRSF-derived linker and transmembrane domains in CAR T function.
Citation Format: Dina Schneider, Ying Xiong, Darong Wu, Boro Dropulic, Rimas Orentas. Plasma membrane spanning and linker-domains from tumor necrosis factor receptor superfamily (TNFRSF) proteins provide novel functionality to chimeric antigen receptors (CARs) expressed in human T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3746. doi:10.1158/1538-7445.AM2017-3746</jats:p
Gene-Based Immunotherapy for Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome
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Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Gene-Based Immunotherapy for Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome
No full textAppropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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