Applied Tumor Immunity

T cell receptor (TCR) discovery and T cell production 

We aim for the development and routine application of personalized TCR gene-engineered adoptive T cell therapies (ACT) targeting individual- as well as shared patient-derived neoepitopes. Based on whole exome or whole genome and tumor mRNA sequencing data, point mutations as well as frameshift mutations are identified and the most promising neoepitopes for each of the patients' six MHC-I (HLA-A, -B, or -C) and/or MHC II molecules are predicted by our pipeline. This state-of-the-art tumor mutanome analysis and in silico T cell epitope prediction is combined with our highly sensitive peptide-loaded MHC-multimer-guided antigen-specific T cell discovery workflow for the identification of epitope-specific TCRs. Our own robust pMHC in-house production platform outperforms commercially available reagents and allows us to provide complete coverage of the individual patients' HLA allotypes. We identify rare neoepitope-reactive T cells directly from peripheral blood, or after in vitro peptide restimulation, in a highly sensitive, multiplex dual-color pMHC-I multimer staining approach followed by T cell single-cell sequencing after systematically evaluating libraries of predicted mutant peptides for successful MHC-I complex binding.

By incorporating DNA-barcoded pMHC-I multimer reagents into the workflow, we link multiplexed tumor antigen recognition with their associated TCR repertoire and T cell differentiation phenotype at single cell resolution, which further improves the selection of TCR/antigen pairs for validation prior to their usage in an ACT. The rigorous implementation of peptide-loaded MHC-I multimer library screenings improved the success rates for the discovery of personalized neoepitope/MHC-I-specific TCR leading to the successful identification and validation of several neoepitope-specific TCRs across various solid tumor entities.

Contact: Marten Meyer, PhD - marten.meyer(at)dkfz-heidelberg.de

Large-scale clinical grade T cell production

We have established manufacturing protocols for the GMP production of CAR-T cells and transgenic TCR-T cells using the semi-automated manufacturing platform CliniMACS Prodigy from Miltenyi Biotec. Protocols are available for the lentiviral vector based production as well as for production using DNA-plasmid vectors. With strong support by the Dietmar-Hopp-Foundation we envision to establish a TCR discovery lab and GMP manufacturing facility for cellular medical products in 2025. This will enable us to develop innovative therapy approaches and produce study drugs for Phase I trials at the NCT, the UKHD, for partner sites within the NCT network as well as to serve as manufacturer for approved cellular drugs.

Contact: Patrick Schmidt, PhD - patrick.schmidt(at)nct-heidelberg.de 

The translational research program of the NEOMUN trial ("NEOadjuvant anti-PD-1 imMUNotherapy in resectable NSCLC: The NEOMUN Trial") is supported by NCT POC trial funding and is carried out in the CCU/NCT 3.0 TME Unit in collaboration with PD Dr. M. Eichhorn and colleagues (Surgery Department, Thoraxklinik Heidelberg). A major aim is the analysis of possible therapy-associated changes in different tumor regions (e.g. core vs. border), lymph nodes or healthy lung tissue and the potential identification of predictive markers.

Contact: Inka Zörnig, PhD - inka.zoernig(at)nct-heidelberg.de | Pornpimol Charoentong, PhD - pornpimol.charoentong(at)nct-heidelberg.de 

The IReP trial ("Immune Response Prediction" trial; funded by the Dietmar-Hopp Foundation) is an exploratory study evaluating the potential of immune signature profiling for predicting response to neoadjuvant chemoimmunotherapy in patients with resectable stage II/III non-squamous NSCLC. An in depth analysis of the tumor microenvironment and genomic alterations is performed in pre- and post-treatment tissue and data is correlated with response as defined by Major pathologic response. The trial is performed in collaboration with PD Dr. M. Eichhorn (Department of Surgery, Thoraxklinik).

Contact: Inka Zörnig, PhD - inka.zoernig(at)nct-heidelberg.de | Pornpimol Charoentong, PhD - pornpimol.charoentong(at)nct-heidelberg.de