TY  - JOUR
A1  - Sonntag, Katja
A1  - Hashimoto, Hisayoshi
A1  - Eyrich, Matthias
A1  - Menzel, Moritz
A1  - Schubach, Max
A1  - Döcker, Dennis
A1  - Battke, Florian
A1  - Courage, Carolina
A1  - Lambertz, Helmut
A1  - Handgretinger, Rupert
A1  - Biskup, Saskia
A1  - Schilbach, Karin
T1  - Immune monitoring and TCR sequencing of CD4 T cells in a long term responsive patient with metastasized pancreatic ductal carcinoma treated with individualized, neoepitope-derived multipeptide vaccines: a case report
JF  - Journal of Translational Medicine
N2  - Background
Cancer vaccines can effectively establish clinically relevant tumor immunity. Novel sequencing approaches rapidly identify the mutational fingerprint of tumors, thus allowing to generate personalized tumor vaccines within a few weeks from diagnosis. Here, we report the case of a 62-year-old patient receiving a four-peptide-vaccine targeting the two sole mutations of his pancreatic tumor, identified via exome sequencing.

Methods
Vaccination started during chemotherapy in second complete remission and continued monthly thereafter. We tracked IFN-γ+ T cell responses against vaccine peptides in peripheral blood after 12, 17 and 34 vaccinations by analyzing T-cell receptor (TCR) repertoire diversity and epitope-binding regions of peptide-reactive T-cell lines and clones. By restricting analysis to sorted IFN-γ-producing T cells we could assure epitope-specificity, functionality, and TH1 polarization.

Results
A peptide-specific T-cell response against three of the four vaccine peptides could be detected sequentially. Molecular TCR analysis revealed a broad vaccine-reactive TCR repertoire with clones of discernible specificity. Four identical or convergent TCR sequences could be identified at more than one time-point, indicating timely persistence of vaccine-reactive T cells. One dominant TCR expressing a dual TCRVα chain could be found in three T-cell clones. The observed T-cell responses possibly contributed to clinical outcome: The patient is alive 6 years after initial diagnosis and in complete remission for 4 years now.

Conclusions
Therapeutic vaccination with a neoantigen-derived four-peptide vaccine resulted in a diverse and long-lasting immune response against these targets which was associated with prolonged clinical remission. These data warrant confirmation in a larger proof-of concept clinical trial.
KW  - pancreatic carcinoma
KW  - therapeutic vaccines
KW  - neoepitope-derived peptides
KW  - T-cell responses
KW  - CDR3 sequences
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239276
VL  - 16
ER  - 
TY  - JOUR
A1  - Weisschuh, Nicole
A1  - Mayer, Anja K.
A1  - Strom, Tim M.
A1  - Kohl, Susanne
A1  - Glöckle, Nicola
A1  - Schubach, Max
A1  - Andreasson, Sten
A1  - Bernd, Antje
A1  - Birch, David G.
A1  - Hamel, Christian P.
A1  - Heckenlively, John R.
A1  - Jacobson, Samuel G.
A1  - Kamme, Christina
A1  - Kellner, Ulrich
A1  - Kunstmann, Erdmute
A1  - Maffei, Pietro
A1  - Reiff, Charlotte M.
A1  - Rohrschneider, Klaus
A1  - Rosenberg, Thomas
A1  - Rudolph, Günther
A1  - Vámos, Rita
A1  - Varsányi, Balázs
A1  - Weleber, Richard G.
A1  - Wissinger, Bernd
T1  - Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing
JF  - PLoS ONE
N2  - Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes.
KW  - mutation detection
KW  - retinal dystrophies
KW  - next generation sequencing
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167398
VL  - 11
IS  - 1
ER  -