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IRTG: Integrated Research Training Group SFB 685  / Actual PhD & MD scholarship holder

MD scholarship holder: Sarah Schröder (MD)

Name:

Sarah Schröder (MD)

Project:

C03

Supervisor:

Prof. P. Lang, Dr. C. Seitz, Dr. P. Schlegel

Email

Opens window for sending emailsarah.schroeder(@)med.uni-tuebingen.de

Scholarship:

01.01.2017 - 30.06.2017

Abstract:

Targeting migrating cancer stem cells by chimeric antigen receptor expressing T-cells - a comprehensive qualitative and functional analysis

Metastatic disease accounts for approximately 90% of cancer related deaths in solid malignancies. In the process of metastatic dissemination, cancer cells trans-differentiate, a process termed epithelial to mesenchymal transition (EMT), in order to invade surrounding tissue and migrate throughout the body. Further they acquire stem-like traits that allow them not only to re-populate cancerous tissue and form distant metastasis, but also to survive under hostile conditions and resist conventional therapeutic intervention like chemotherapy, radiation as well as certain targeted therapies. 

An adapter chimeric antigen receptor (aCAR) expressed by transduced T-cells, combined with an adapter molecule, can recognize extracellular antigens expressed on cell surface, and cause the destruction of targeted cells through T-cell activation. While the transduced T-cells persist in the patient, their activity can be controlled by adding, removing, or changing adapter molecules, or their dose. Being a living and flexible drug, aCAR-T-cells, targeting CSC, could offer a great opportunity for permanent cancer control.

The first goal of the present study is to screen breast cancer cells for their expression of 22 cancer stem cell (CSC) associated antigens, using flow cytometry. The expression will be measured in established cell lines, primary patient material and cells undergoing EMT after EMT-induction. Using a stem cell reporter gen, which expresses destabilized GFP in the presence of SOX2 and OCT4, cancer cells in a stem-like condition can be monitored. Furthermore their antigen expression can be compared to the rest of the cancer cell population. 

In a second step, the suitability of the antigens as a target for aCAR-T-Cell induced lysis will be functionally tested. Lysis will be monitored using real time (impedance based) cell cytotoxicity assay (RTCA xCELLigence).

The results of this study will provide a comprehensive profiling of the antigen landscape on breast cancer and breast cancer stem cells. Further it will identify promising targets for aCAR-T therapy to prevent metastasis formation, resistance to therapy and relapse. Based on the results of this study, aCAR-Ts in combination with adapter molecules will be evaluated in vivo using a mouse model for spontaneous metastasis formation. With this work, we aim to establish a screening platform for individualized immuno-targeting.


MD scholarship holder: Isabelle Ehnes (MD)

Name:

Isabelle Ehnes (MD)

Project:

Supervisor:

Gundram Jung/ Helmut Salih

Email

Opens window for sending emailisa7up(@)arcor.de

Scholarship:

01.01.2017 - 30.06.2017

Abstract:

Off target activation by proprietary bispecific PSMAxCD3 antibody CC1

Bispecific CD3 stimulating antibodies show the undesirable side effect of “off target” activation of T-cells in absence of tumor cells. Recent dissertations demonstrated that antibodies against several adhesion-molecules can avoid this effect, but unfortunately they have no clinical approval. However antibodies against cytokines like TNF α and IL6 are clinical applied. This project will figure out possibilities to suppress the off target activation without impair the on target activity in the presence of tumor cells. As a final goal these results will influence the conception of the first clinical polit study with the proprietary bispecific PSMAxCD3 antibody in order to clarify if cytokine inhibitory antibodies are a useful co-medication.


MD scholarship holder: Timo Munz (MD)

Name:

Timo Munz (MD)

Project:

Supervisor:

Dominik Schneidawind / Hans-Georg Rammensee

Email

Opens window for sending emailtimomunz(@)hotmail.de

Scholarship:

01.10.2016 - 31.03.2017

Associated:

01.04.2017 -

Abstract:

Invariant natural killer T cells and immune tolerance after allogeneic hematopoietic cell transplantation

Graft-versus-host disease (GVHD) is characterized by a donor lymphocyte-mediated destruction of host tissues and constitutes a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Invariant natural killer T cells (iNKT cells) are a potent immunoregulatory T-cell subset. In murine GVHD models adoptive transfer of iNKT cells protects recipient animals from lethal GVHD through a robust expansion of CD4+CD25+FoxP3+ regulatory T cells (Tregs) in secondary lymphoid organs and GVHD-target tissues (Schneidawind et al. 2014, Schneidawind et al. 2015). In this project, phenotypic and functional properties of human iNKT cells will be assessed post allogeneic HCT using glycolipid-loaded CD1d tetramers and single cell sorting technologies. This aims to elucidate key molecules that are crucial for the induction of immune tolerance. Furthermore, we will recapitulate the reconstitution of iNKT cells after allogeneic HCT. Based on our findings, iNKT cells might constitute a platform where specific manipulation of distinct pathways results in amelioration of GVHD and consequently, improves outcomes after allogeneic HCT.

References: 

Bendelac, A., P. B. Savage and L. Teyton (2007). "The biology of NKT cells." Annu Rev Immunol 25: 297-336.

Schneidawind, D., J. Baker, A. Pierini, C. Buechele, R. H. Luong, E. H. Meyer and R. S. Negrin (2015). "Third-party CD4+ invariant natural killer T cells protect from murine GVHD lethality." Blood 125(22): 3491-3500.

Schneidawind, D., A. Pierini, M. Alvarez, Y. Pan, J. Baker, C. Buechele, R. H. Luong, E. H. Meyer and R. S. Negrin (2014). "CD4+ invariant natural killer T cells protect from murine GVHD lethality through expansion of donor CD4+CD25+FoxP3+ regulatory T cells." Blood 124(22): 3320-3328. 


PhD scholarship holder: Juliane Schneider (PhD)

Name:

Juliane Schneider (PhD)

Project:

Z05

Supervisor:

Cécile Gouttefangeas

Email

Opens window for sending emailschneider_juliane(@)gmx.de

Scholarship:

01.10.2016 - 30.06.2017

Associated:

Abstract:

T cell immunity upon checkpoint inhibition

The recent success of checkpoint inhibitors in the clinic has demonstrated that restoring T cell immunity leads to tumor control in a substantial fraction of patients. Current data indicates that essentially tumor neoantigens are targeted by checkpoint antibodies; however no definitive biomarkers of clinical response have been identified so far. Our project investigates the effect of prolonged checkpoint blockade on the immune system in cancer patients, with a focus on T cell functionality and antigen-specificity.


MD scholarship holder: Léo März (MD)

Name:

Léo März (MD)

Project:

Supervisor:

Stefan Stevanović

Email

Opens window for sending emailleo.maerz(@)gmx.de

Scholarship:

01.10.2016 - 31.03.2017

Associated:

01.04.2017 -

Abstract:

A consensus pool of T-cell epitopes from Adenoviral antigens

Adenoviral infections are widespread in the population and usually persistent. Human Adenovirus (HAdV) has been described to lead to severe pathogenesis in immune compromised individuals with a high mortality rate. The most prevalent species are HAdV 2 and HAdV 5 of Mastadenovirus serotype C. The infection is controlled by the cellular immune system, thus low T-cell counts are correlated with severity of infection and mortality. In such cases, the adoptive T-cell transfer has proved to be a promising therapeutic strategy.

This project will identify T-cell epitopes derived from adenoviral proteins and restricted by all common types of HLA molecules. As a final goal, an HAdV consensus pool will be established which will stimulate HAdV-specific CD4 and CD8 T cells of virtually every donor. 


PhD scholarship holder: Claudia Tandler (PhD)

Name:

Claudie Tandler (PhD)

Project:

A07

Supervisor:

Helmut Salih

Email

Opens window for sending emailClaudia.tandler(@)med.uni-tuebingen.de

Scholarship:

01.01.2016 - 31.12.2016

Associated:

01.01.2017 -

Abstract:

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PhD scholarship holder: Jennifer Rebecca Richardson (PhD)

Name:

Jennifer Rebecca Richardson (PhD)

Project:

A03

Supervisor:

Stella Autenrieth

Email

Opens window for sending emailjenny(@)richardsons.de

Scholarship:

01.01.2016 - 31.12.2016

Associated:

01.01.2017 -

Abstract:

Multimodal imaging approaches to investigate myeloid cell development during sterile or pathogen-induced inflammation

Dendritic cells (DCs), monocytes and neutrophils are critical in host defense against infections. Patients with sepsis display reduced circulating and splenic DCs and impaired DC function that may contribute to prolonged immune suppression and infection exacerbation. This effect is due to reduced hematopoietic progenitors committed to the DC lineage upon infection, while monopoesis is induced. Our aim is to gather new insights in the host-pathogen-interactions focusing on the myeloid cell development, and differentiating between sterile and pathogen-induced inflammation. Further the investigation of the molecular mechanisms underlying the induction of monopoiesis at the expense of DC differentiation at the single cell level will help to understand basic myeloid cell biology, but may also identify new therapeutic targets/diagnostic markers in infectious diseases.


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