Immune monitoring and TCR discovery
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Dr. Isabel Poschke
Teamleader
"We perform deep profiling of antigen-specific immune responses to define features of successful anti-tumor immunity in cancer patients."
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Our Research
The immune monitoring unit is located at the NCT and analyzes samples from cancer patients of various entities enrolled in clinical trials. We are specialized in monitoring antigen specific adaptive immune responses and contribute to a number of phase I and phase II clinical trials in Heidelberg, across Germany, as well as to multinational trials.
In order to maximize the knowledge gained from clinical samples, our research aims to decipher characteristics of successful T cell responses that enable effective immunotherapy, or that are induced during the course of an immunological intervention. We are particularly interested to understand T cell receptor (TCR) repertoire composition and dynamics, its change during treatment and the hallmarks of T cells carrying tumor-antigen specific receptors. As part of these efforts, we work towards a warehouse of tumor-reactive TCRs, both shared- and unique-neoantigen-specific, that could be applied therapeutically.
Our projects focus on samples of patients with brain tumors, either as primary tumor site or as site of metastasis from other solid tumor entities.
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TCR Discovery Projects
We established a modular platform for the identification of tumor-specific T cell receptors (TCRs). Using epitope-specific expansion cultures (ESPEC) with subsequent identification of TCRs (SUIT) by bulk and optional single-cell TCR sequencing, we identify T cell clones with reactivity against an epitope-of-interest.
We have performed ESPEC-SUIT for >30 patients, covering hundreds of epitopes and observed robust expansion of both CD4+ as well as CD8+ T cell responses. In a sub-cohort of ten patients we selected 341 ESPEC-SUIT-derived TCRs for cloning and in vitro functional validation from >2000 candidates and confirmed antigen-reactivity for >75%.
By tracing of TCR sequences, candidate and validated antigen-specific TCRs can be mapped to other datasets, allowing us to assess for example their response to therapeutic interventions such as vaccination, and to profile their phenotype within tissue samples.
The recurrent R132H mutation in isocitrate dehydrogenase 1 (IDH1) is a driver mutation found in 70-80% of gliomas, making it an attractive therapeutic target. Our group previously developed a long peptide vaccine targeting IDH1R132H, which induced a strong immune response in pre-clinical models as well as two phase I clinical trials (NOA16 and NOA21). We performed detailed analysis of IDHR132H specific T cell responses and using the ESPEC-SUIT platform establish a warehouse of IDH1R132H-reactive TCRs in the HLA-diverse patient population that received the vaccine.
We are following IDH1R132H specific T cells longitudinally in the blood and, based on single sequencing results of tumor tissue, defined a gene-expression signature identifying this tumor-reactive T cell subset. CD4 and CD8 T cell-derived IDH1R132H reactive TCRs are undergoing characterization with respect to affinity and HLA restriction to identify TCRs associated with treatment response and lead candidates for future clinical translation.
The number of shared tumor antigens that can be targeted by T cell-based therapies is limited. At the same time, sequencing-based interrogation of tumor composition is becoming common practice, allowing the discovery of patient-individual neoepitopes derived from mutation or fusion events.
Using selected patient cases, we are studying T cell responses to such ‘private’ neoepitopes, to understand the frequency, breadth and quality of T cell responses present endogenously or after application of individualized vaccines. To enable future personalized TCR-based therapies manufactured for individual patients, we are collaborating with the immunogenomics team to streamline assays for rapid TCR discovery.
Gene-fusion events hold large potential to generate immunogenic neoepitope. We are evaluating the immunogenicity of patient-individual, as well as disease-specific recurrent fusions events in multiple different tumor entities using our ESPEC-SUIT platform. TCR repertoires reactive to immunogenic fusions are i) characterized by in vitro TCR expression, specificity testing and definition of exact target antigens and ii) traced longitudinally in blood and tissue samples. We aim to establish TCR warehouses targeting antigens derived from recurrent break-points and covering common HLA alleles to make the therapeutically available to broad patient cohorts.
Learn more about standardized immune monitoring of clinical trials
Publications
Tan CL, Lindner K, Boschert T, Meng Z, Rodriguez Ehrenfried A, De Roia A, Haltenhof G, Faenza A, Imperatore F, Bunse L, Lindner JM, Harbottle RP, Ratliff M, Offringa R, Poschke I, Platten M, Green EW.
Salek M, Förster JD, Becker JP, Meyer M, Charoentong P, Lyu Y, Lindner K, Lotsch C, Volkmar M, Momburg F, Poschke I, Fröhling S, Schmitz M, Offringa R, Platten M, Jäger D, Zörnig I, Riemer AB
Boschert T, Kromer K, Lerner T, Lindner K, Haltenhof G, Tan CL, Jähne K, Poschke I, Bunse L, Eisele P, Grassl N, Mildenberger I, Sahm K, Platten M, Lindner JM, Green EW.
Meyer M, Parpoulas C, Barthélémy T, Becker JP, Charoentong P, Lyu Y, Börsig S, Bulbuc N, Tessmer C, Weinacht L, Ibberson D, Schmidt P, Pipkorn R, Eichmüller SB, Steinberger P, Lindner K, Poschke I, Platten M, Fröhling S, Riemer AB, Hassel JC, Roberti MP, Jäger D, Zörnig I, Momburg F.
Meng Z, Ehrenfried AR, Tan CL, Steffens LK, Kehm H, Zenz S, Lauenstein C, Paul A, Schwab M, Förster JD, Salek M, Riemer AB, Wu H, Eckert C, Leonhardt CS, Strobel O, Volkmar M, Offringa R, Poschke I
Grassl N, Poschke I, Lindner K, Bunse L, Mildenberger I, Boschert T, Jähne K, Green EW, Hülsmeyer I, Jünger S, Kessler T, Suwala AK, Eisele P, Breckwoldt MO, Vajkoczy P, Grauer OM, Herrlinger U, Tonn JC, Denk M, Sahm F, Bendszus M, von Deimling A, Winkler F, Wick W, Platten M, Sahm K.
Grassl N, Sahm K, Süße H, Poschke I, Bunse L, Bunse T, Boschert T, Mildenberger I, Rupp AK, Ewinger MP, Lanz LM, Denk M, Tabatabai G, Ronellenfitsch MW, Herrlinger U, Glas M, Krex D, Vajkoczy P, Wick A, Harting I, Sahm F, von Deimling A, Bendszus M, Wick W, Platten M.
Lu KH, Michel J, Kilian M, Aslan K, Qi H, Kehl N, Jung S, Sanghvi K, Lindner K, Zhang XW, Green EW, Poschke I, Ratliff M, Bunse T, Sahm F, von Deimling A, Wick W, Platten M, Bunse L.
Bunse L, Rupp AK, Poschke I, Bunse T, Lindner K, Wick A, Blobner J, Misch M, Tabatabai G, Glas M, Schnell O, Gempt J, Denk M, Reifenberger G, Bendszus M, Wuchter P, Steinbach JP, Wick W, Platten M.
Platten M, Bunse L, Wick A, Bunse T, Le Cornet L, Harting I, Sahm F, Sanghvi K, Tan CL, Poschke I, Green E, Justesen S, Behrens GA, Breckwoldt MO, Freitag A, Rother LM, Schmitt A, Schnell O, Hense J, Misch M, Krex D, Stevanovic S, Tabatabai G, Steinbach JP, Bendszus M, von Deimling A, Schmitt M, Wick W.
Poschke IC, Hassel JC, Rodriguez-Ehrenfried A, Lindner KAM, Heras-Murillo I, Appel LM, Lehmann J, Lövgren T, Wickström SL, Lauenstein C, Roth J, König AK, Haanen JBAG, van den Berg J, Kiessling R, Bergmann F, Flossdorf M, Strobel O, Offringa R.
Scientist Team
4 Employees
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Dr. Isabel Poschke
Team Leader
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Dr. Katharina Lindner
PostDoc
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Saskia Stange
PhD Student
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Julian Hlawatsch
MD Student
Get in touch with us
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