ORGANISATION/COMPANYCentro de Biología Molecular Severo Ochoa
RESEARCH FIELDBiological sciencesChemistryEngineering › Biomaterial engineeringEngineering › Biomedical engineeringMedical sciencesPhysics › BiophysicsPhysics › Optics
RESEARCHER PROFILEFirst Stage Researcher (R1)
APPLICATION DEADLINE01/05/2017 23:00 - Europe/Brussels
LOCATIONMultiple locations, see work locations below.
TYPE OF CONTRACTTemporary
HOURS PER WEEK36 - 40 according to country
OFFER STARTING DATE01/09/2017
EU RESEARCH FRAMEWORK PROGRAMMEH2020 / Marie Skłodowska-Curie Actions
MARIE CURIE GRANT AGREEMENT NUMBER721358
The H2020-MSCA-funded Innovative Training Network EN-ACTI2NG (www.enacti2ng-itn.eu) builds on recent clinical evidence that T cells expressing engineered tumor-specific immune receptors can eradicate tumors that do not respond to conventional treatment. This important therapeutic approach is in a very early phase of development and requires a well-trained workforce to address challenges such as development of tumor-specific receptors for a wider array of tumors, improvement in efficiency of these receptors, better on/off-target toxicity safety profiles and more efficient transfer of basic research findings to the clinic.
- to train early stage students with expertise in development of new and improved T cell-mediated tumor immunotherapies
- to teach them to facilitate communication between stakeholders (scientists, clinicians, industry, patients and the general public)
- to improve T cell-mediated tumor immunotherapy by the development of new tumor-specific immune receptors and enhancing their function by identifying and modifying their molecular mechanism of action.
The aims will be reached via 10 individual research projects that rely on the complementary expertise of the participating groups. Training in research-specific skills, career development and communication will also be offered.
All research projects should give rise to a PhD and all PIs have arranged access to doctoral programs of the hosting or affiliated institutions.
PhD1: Determination of CD3 domains involved in TCR nanoclustering to improve T cell sensitivity
PI: Hisse M van Santen, CBMSO, Madrid ES
T cell activation depends on ligand recognition by the TCR. This interaction is of low affinity, but T cells are exquisitely sensitive and specific. Our previous work has shown that T cells achieve and regulate this sensitivity by TCR nanocluster formation. The project aims to define molecular interactions involved in TCR nanoclustering in human T cells and test the effect of disruption or enhancement of these interactions on T cell activation and tumor killing capacity. These findings can then be applied to therapeutically relevant TCR-expressing human T cells.
PhD2: The role of novel TCR‐CD3 interaction partners for TCR and CAR function
PIs: Susana Minguet and Wolfgang Schamel, Faculty of Biology and Center of Chronic Immunodeficiency, University of Freiburg, DE
The TCR complex has multiple protein‐protein interaction sites that bind to downstream signaling molecules. We have identified novel interaction proteins, such as Kidins220 which couples the TCR to B‐Raf signaling and is crucial for sustained Erk activation and full T‐cell activation. Nck and other proteins bind to the proline‐rich sequence (PRS) in CD3ε and modulate TCR phosphorylation and downstream signaling. We will explore the function of these molecules in T‐cell activation, use this knowledge for the development of novel CARs and test these CARs in human αβ and γδ T cells.
PhD3: Combinatorial antigen recognition by two tumor-specific CARs with split signaling moieties
PI: Hinrich Abken, Uniklinik Cologne, DE
Since most CAR-targeted “tumor associated antigens” are not only expressed by cancer cells but also by healthy cells, combinatorial recognition of two antigens on cancer cells may overcome the risk of severe auto‐immunity. Thus, the identification of molecular mechanisms which result in productive (co‐)synapse formation of two CARs of different specificities and signal complementation of these CARs is necessary. The project builds on our recently developed strategy of combinatorial antigen recognition by two CARs which deliver the primary TCR signal and the CD28 costimulation, respectively.
PhD4: Identification and testing of therapeutically relevant high affinity TCRs directed against new B‐cell tumor‐associated target antigens
PI: Mirjam Heemskerk, LUMC, Leiden, NL
Antibody‐mediated immunotherapy and CAR engineered T‐cells against CD19 and CD20 show great clinical benefit in the treatment of B cell tumors. However, loss or absence of these molecules on other lymphoid tumors restricts their application. Thus, new lineage‐specific or B‐cell tumor associated target antigens have to be identified. We recently isolated a TCR specific for a B cell-specific transcription factor that reacts against primary B cell leukemias, lymphomas and multiple myeloma while sparing healthy non‐B cell hematopoietic cells. This TCR is potentially useful to treat B cell tumors using TCR gene therapy. We will use the same strategy to identify more high affinity TCRs directed against lineage-specific antigens.
PhD5: Visualize, quantify and categorize CAR‐T‐cell antigen recognition
PI: Johannes Huppa, Institute for Hygiene and Applied Immunology, Medical University Vienna, AT
Little is known how CAR T cells recognize antigens. Knowledge of recognition events is needed for the rational design of safe and more selective CARs. We will devise a planar glass‐supported molecular imaging platform, which serves as a surrogate target cell for CAR T cells, to quantify synaptic receptor binding and signaling events in living CAR T cells, and resolve membrane architecture with single molecule resolution. Together with PhD6 and PhD7 we will extend this system for its use in automated microfluidics devices as a means to select individual CAR T cells based on synaptic and cytoplasmic signaling and effector functions and profile them in depth for T cell differentiation and gene transcription.
PhD6: Single molecule mobility and protein‐protein interactions in CAR T cells
PI: Gerhard Schütz, Institute of Applied Physics, Vienna University of Technology, AT
Many proteins have been defined that contribute to recognition of antigens by a T cell and its response, but mechanistic understanding of their function is completely missing. We will use single molecule tracking and two color superresolution microscopy to quantify the interactions between the different membrane proteins on CAR T cells at milliseconds time resolution, allowing determination of the stoichiometry of the participating molecules and relative positioning at a few tens nanometer accuracy. Ultimately, targeted delivery of cells to imaging platforms will enhance throughput in single molecule experiments. We thus assist PhD5 and PhD7 in the development of a microfluidics system.
PhD7: microfluidic chip development for microscopy-assisted observation and selection of single cells
PI: Marco Lindner, STRATEC Consumables GmbH, Anif, AT
CAR T cells can respond very differently to identical stimuli, and build up synapses of highly heterogeneous phenotypes. We will develop a microfluidic biochip prototype allowing for highly automated analysis of individual cells, including targeted delivery to a microscope platform, characterization by fluorescence microscopy and removal of interesting cells for further characterization by other techniques. The project includes design of the biochip and i/o system, mastering of the biochip, hot embossing into thermoplastics, integration of the biochip in the i/o system and microscopy platform, and the ultimate application for our cell biological experiments.
PhD8: Identification of TCR/costimulatory aptamers to generate an artificial T‐cell signalosome aptamer scaffold.
PI: Fernando Pastor, CIMA, Pamplona, ES
Aptamers are DNA‐ or RNA‐based single‐stranded oligonucleotides that fold into complex structures allowing them to bind their targets with high affinity and specificity. Their nucleic acid nature provides advantages over antibodies, including easier production under GMP conditions, low antigenicity, chemical versatility and small size. Aptamers are thus emerging as a novel immunotherapy platform. We previously showed the potency of aptamers to modulate the immune response by targeting murine costimulatory receptors. We will agonistic TCR aptamers to induce TCR signalosome activation by and combine them with costimulatory agonistic aptamers to trigger a potent immune response for cancer immunotherapy.
PhD9: Selection of CD8 co‐receptor variants for optimization of TCR gene therapy
PI: Linda Wooldridge, Faculty of Medical and Veterinary Sciences, University of Bristol, UK
TCRs of CD8 T cells recognize foreign peptides presented by Major Histocompatibility Complex Class I (pMHCI) molecules. Recognition is enhanced by simultaneous binding of the CD8 co-receptor. In the context of anti-cancer immunotherapy, a common problem is that anti‐cancer TCRs are often characterized by weak affinities. This might be overcome by co‐expressing such TCRs with a high affinity variant of the CD8 co‐receptor to enhance the cancer-specific T‐cell response. Our data suggests that the optimal pMHCI/CD8 interaction strength varies between different anti‐cancer TCRs. Thus, we will identify the optimal high affinity CD8 pairing for TCRs specific for common tumor antigens.
PhD 10: Novel CAR formats with enhanced signaling and tumor recognition properties
PI: Michael Hudecek, Uniklinikum Würzburg, DE
We previously showed that affinity of the CAR antigen‐binding domain and design and length of the extracellular CAR spacer domain affect tumor recognition. We have established new ultra‐adjustable CAR spacer and antigen‐binding domain configurations to replace the conventional scFv format. Both parameters will be evaluated in library‐based screening assays to identify receptor designs with optimal anti‐tumor function. We will analyze these novel CARs in vitro and in murine tumor models. Together with PhD5 we will extend our data with visual and quantitative analysis of CAR signaling, membrane organization and clustering via superresolution microscopy.
The ESRs will be employed under a 3 year contract according to the legislation of the hosting country and will be covered under the social security scheme of the hosting country. They will receive a Living Allowance (3000 – 3200 €/month gross salary), a Mobility Allowance (600€/month) and a Family Allowance (500€/month where applicable) compliant with the applicable EC Marie Skłodowska-Curie Actions – ITN general conditions. See the website of the EN-ACTI2NG consortium for more details. Please note that contributions to social security (both employer and employee part) and taxes will be deducted according to the applicable regulations of each country.
As mandated by EU regulations, applicants shall, at the time of recruitment by the host organization, be in the first four years (full-time equivalent research experience) of their research careers and have not been awarded a doctoral degree. They should also fulfill the mobility rule: at the time of recruitment by the host organization, researchers must not have resided or carried out their main activity (work, studies, etc.) in the country of their host organization for more than 12 months in the 3 years immediately before the hiring date. Compulsory national service and/or short stays such as holidays are not taken into account. All recruiting institutions are equal opportunity employers and woman are strongly encouraged to apply.
Applicants are strongly encouraged to contact the individual group leaders before submitting their applications (see our website www.enacti2ng-itn.eu for contact details). Applications have to include a CV (no gap time will be allowed in order to verify fulfillment of the mobility and 3 year rules), including a valid e-mail address and telephone number, a copy of valid passport or identity card, a copy of university degree and master or equivalent degree (or statement by program director indicating the date of award of the degree), a transcript of academic grades (including an explanation of the grading system), a letter of motivation, one or more recommendation letters and a list of the 3 projects they are most interested in, listing the project numbers and titles in order of preference. These documents should be sent in a single pdf file to the consortium’s e-mail address (firstname.lastname@example.org) mentioning in the subject line: EN-ACTI2NG application and the numbers of the 3 projects in preferred order (e.g, “EN-ACTI2NG application PhD5, PhD8, PhD2”). After a first check of fulfillment of the EU-mandated eligibility criteria and requested documentation, CVs will be forwarded to the group leaders. Group leaders will contact the best 3 applicants for each position for an interview via Skype and/or will invite them for an interview. You may be contacted by various group leaders.
The training programme comprises:
- Research training activities, performed locally, leading to award of the PhD title.
- Secondments in
- Scientific/technical training courses and activities performed locally and at the project level to train the students in scientific topics, advanced technology and methodologies necessary for the project implementation.
- Transferable skills training to prepare the ESRs for an academic or industrial career will be provided through local and joint training courses.
- Scientific events, such as 3 anual project meetings and 1 mid-term meeting, where the fellows will be required to present their achievements and progress to a senior audience, and implication in organization of an international scientific meeting.
- Extensive training in communication skills provided by our partner Scienseed
Web site for additional job details
REQUIRED EDUCATION LEVELBiological sciences: Master Degree or equivalentChemistry: Master Degree or equivalentEngineering: Master Degree or equivalentMedical sciences: Master Degree or equivalentPhysics: Master Degree or equivalent
REQUIRED LANGUAGESENGLISH: Good
Applicants must be in possession of/ in the last part
of the program leading to the degree (usually the Master Degree) in Biological
Sciences, Chemistry, (Bio-)Physics, Engineering, Medical Sciences which would
formally entitle them to embark on a doctorate, either in the country in which
the degree was obtained or in the country in which the researcher will be
recruited. The exact requirements to start the PhD program vary from university
to university, and have to be clarified in each individual case. Students that
are still in the course of obtaining the qualifying degree should include an official
declaration by their program director specifying the date at which the degree
will be awarded.
EURAXESS offer ID: 165225
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