Frankfurt Rhine-Main Metropolitan Area
In my profession for more than 2 decades I was focusing on cellular immunotherapy of cancer. Here, I was dominantly interested in molecular optimization strategies (i.e. protein design) of tumor and virus antigen-specific immunoreceptors such as TCRs and CARs for expression in human T-cells. 2 ultimate goals which I originally initiated and was aiming at were 1. to sustain antigen-specificity of introduced TCRs in the presence of natural TCRs, i.e. to prevent TCR mispairing, and 2. to achieve optimal T-cell signaling of CAR T-cells in a more physiological manner, i.e. designing TCR-like CARs dependent on endogenous CD3. Here, I found out very early that T-like CARs have a higher antigen sensitivity than classical CARs, a unique feature being confirmed meanwhile by others such as M. Sadelains' lab (Hamieh, Canc. Discov. 2023). This will have important implications for tackling minimal residual disease. In a second priority, I established different gene transfer systems for their heterologous expression such as retroviral transduction or CRISPR/NHEJ - mediated TCR knock outs and CRISPR/HDR - mediated TCR/CAR knock ins in our laboratory. Additionally, I apply ivt-RNA - titrated expression of immunoreceptors and antigens, which allows for the reliable determination of their fine-specificity and efficacy. At the moment, I am testing safeguards introduced into TCR-like CARs and am trying to improve costimulation of TCARs according to the 'and-gate' strategy. Despite my senior status and continuous supervision of students from all faculties in life science, I am still planning, performing and evaluating/presenting experiments by myself in order to sustain my practical skills in new techniques and to judge which envisioned scientific goals are reasonable and feasible. In every new project I tried to cooperate with internal and external groups to expand novel approaches. My Alma Mater offered me great opportunities to proceed in translational research and to present my scientific results in the public (plethora of posters) and peer-reviewed journals. In line with focusing on applied science I also submitted inventions related to immunotherapy of those most have been accepted for rights protection and by now were aquired by biotech companies. On the other hand, I was fond of training students in immunotherapy seminars and practical courses, and to supervise Ph.D.-/Diploma-/M.D.-/B.Sc.-/M.Sc.-students in their theses. Moreover, I was regularly invited to review manuscripts and grants for different international journals and foundations, respectively.
Senior Scientist in a subproject called 'Molecularly optimized antigen specific T cells to be applied in individualized immunotherapy of cancer' granted by the German Federal Ministry of Education and Research (BMBF). I applied for this grant headed by Prof. Dr. Ugur Sahin because of my prior results in developing a novel CD3 complex-dependent CAR specific for ErbB2 tumor antigen which operates in analogy to a natural TCR by means of recruiting all essential CD3 subunits (see previous section: ASGCT 2011). During that funding I redesigned the CD3-dependent CAR specific for tumor antigen Claudin 6 which has been studied under my supervision in depth at UMC of Johannes Gutenberg University Mainz, TRON and BioNTech. The unique feature of a TCR-like CAR is the superior tumor antigen sensitivity demonstrated the first time on my ESGCT poster 2019/Barcelona (see media). This most-likely is due to ideal immunological synapse (IS) formation and thorough CD3 subunit recruitment as opposed to a classical CAR. Most recent projects: 1.) Development of a safeguard into a TCR-like CAR to prevent off-tumor toxicities in the clinic. 2.) CRISPR/Cas-technology to shift T-cell function towards TCARs. 3.) Humanization of the murine Claudin 6-specific antibody: Combination of antibody structure databases with IMGT-based knowledge about antibody assembly. 4.) Eradication of TGFbRII expression by CRISPR/Cas9 genomic editing to leave CAR T-cells unsusceptible for immunosuppressive TGFb. Supervision : - Dora Gulyban (Bachelor thesis in Molecular Biology) - Luca Breiling (Master thesis in Biotechnology) - Khadijeh Alishah (PhD thesis in Biotechnology) - Dr. Matthias Birtel (PhD thesis in Biology) - Janina Caspar (Master thesis in Biomedicine) Expert activities : - KLS, GIF, KWF (grants) - J. Immunol., JTM (manuscripts) - CIMT (chairman, abstracts) Teaching students: - Lecturer in a serial seminar called 'Tumorgenetics' headed by Prof.s Jochen Decker and Walburgis Brenner.
Shared group leader in SFB-432 "Mechanisms of tumor rejection und their therapeutic manipulation" (along with Prof. Dr. Matthias Theobald), and Clinical Research Group (KFO) 183 “Optimized allogeneic lymphocyte therapy” (along with Prof. Dr. Matthias Theobald, and Dr. Carina Lotz or Dr. Hakim Echchannaoui). Writing of a grant proposal to prolong KFO 183 passed revision. Main project: During that time the single chain TCR-format comprising the coexpression of a truncated TCR Calpha-domain for full effector function was tested in vivo in NSG-mice in a fruitful cooperation with NCI/Heidelberg and later on refined by introducing novel engineered disulfide bridges to prevent V-domain dissociation and thus, TCR-mispairing with endogenous TCRs in T-cells. This led to the generation of virus/tumor antigen bispecific TCR T-cells to be adoptively transferred into CMV-positive recipients by DLI (see Pubmed (Oncotarget)). Side projects: In analogy to the newly designed scTCR + Calpha - concept (see Pubmed (Blood)), a novel scCAR + Calpha - format was developed and successfully tested (see Cell Press). This prototypic CAR recruits endogenous CD3 for T-cell effector function instead of being fused to CD3zeta. Identification of A2.1-restricted ErbB2-reactive T-cells from bulk T-cells using a 'Reverse Immunology'-approach. Manipulation of antigen affinity of a p53-specific TCR by site directed mutageneses of TCR's CDR3 region. Supervision : Dr. Diana Knies (PhD thesis in Biology) Dr. Lukas Eckhard (MD thesis) Bc.Sc. Yasmin Djirsarai (Bachelor thesis in Biology) Expert activities : - Gene Therapy (manuscripts) - Blood (manuscript) - J. Translational Medicine (manuscript) - American Association of Cancer Research (manuscript) - Deutsche Krebshilfe (grant) Education: - Lecturer in a serial seminar called 'Tumorgenetics' headed by Prof.s Dr. Jochen Decker and Walburgis Brenner. - Lecturer in a serial practical course for students applying for M. Sc. Biomedicine.
Post-Doc in the sub-project 'Selection and transfer of therapeutic T-cell receptors' headed by Prof. Dr. Matthias Theobald within SFB-432 "Mechanisms of tumor rejection und their therapeutic manipulation" governed by Prof. Dr. Dr. Christoph Huber, and granted by DFG and MAIFOR. My post-doc position was granted by 'Rheinland-Pfalz Innovation' (RPI). My first tasks were aiming at the isolation of the coding sequences of an MDM2 tumor antigen-reactive TCR from a T-cell clone and later on, from a p53 tumor antigen-reactive T-cell clone by elaborated PCR techniques. The TCRs stemmed from (hybrid) A2-transgenic mice to circumvent central tolerance mechanisms in humans and thus, were characterized by an extraordinary high affinity for their tumor antigen (see Pubmed (Nature Immunology and Immunity) - attachments). Later on, I was asked to develop strategies to prevent chain pairing of TCRs introduced into T-cells with the endogenous ones. For this I focused on protein design of the Interface of double chain TCRs (see Pubmed (J. Immunol.) - attachment), or launched a new project relying on a novel single chain TCR - format (see Pubmed (Blood) - attachment in my project lead-section). Supervision: Dr. Frank Schmitz (MD-student Medicine) Dr. Simone Thomas (MD-student Medicine) Dr. Ratna Sari Intan (MD-student Medicine). Education: - Lecturer in a serial seminar called 'Tumorgenetics' taking place 2 times a year and headed by Prof. Dr. Jochen Decker and Prof. Dr. Walburgis Brenner.