Medizinische Universitätsklinik
Innere Medizin II
Hämatologie, Onkologie, klinische Immunologie und Rheumatologie

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Adresse: Otfried-Müller-Straße 10
72076 Tübingen


Personenprofil: 07071 29-82711 Pforte


Telefonnummer: 07071 29-89200 24h Hotline


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Peptid-basierte Immuntherapie

Scientific focus

In recent years the breakthrough clinical success of T-cell based immunotherapy approaches including advances in allogeneic stem cell transplantation, checkpoint inhibitors, CAR T cells, bispecific antibodies and adoptive T-cell transfer have revolutionized treatment of several hematological malignancies (HM). However, still some patients do not respond to available therapeutic strategies at all, others for limited time only. Remaining challenges to augment efficacy of T cell-based immunotherapy are particularly to improve specificity and increase the frequency of anti-tumor immune responses, to reduce toxicity and to expand the spectrum of targetable cancer entities. A rational and promising approach to achieve this goal is peptide-based immunotherapy, which represents a low side-effect approach relying on specific immune recognition of tumor-associated HLA (human leucocyte antigen) presented peptides. In the recent years, our junior research group focused on the identification and characterization of such tumor-associated antigens for hematological malignancies using the approach of direct isolation and mass spectrometric analysis of HLA-presented peptides on the cell surface of leukemia cells. Using this approach we were able identify more than 45,000 HLA class I and II ligands representing more than 10,000 source proteins in acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). To identify broadly represented leukemia-associated antigens that can serve as targets for peptide-based immunotherapy, we developed a novel platform that defines tumor-associated antigens (TAA) based on their exclusive and high frequent representation in the immunopeptidome of HM patients. Hereby we are able to identify several novel, immunogenic leukemia-associated antigens, which are further validated to be broadly and frequently represented across different stages and mutational subtypes, remain stable under standard treatment and are targets for spontaneous memory T-cell responses in HM patient. Based on our data for CLL we have already establish the first multi-center, patient-individualized peptide vaccination trial for CLL patients, which is successfully recruiting since 10/2016 (iVAC-L-CLL01, NCT02802943).

Kontakt

Arbeitsgruppenleitung

frontend.sr-only_#{element.contextual_1.children.icon}: PD Dr. med. Juliane Walz


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E-Mail-Adresse: juliane.walz@med.uni-tuebingen.de


Research Projects


Identification and characterization of tumor-associated antigens in hematological malignancies.

The goal of all projects within our junior research group is to develop clinically effective, low toxicity, peptide-based immunotherapy approaches for the treatment of HM. The first critical issue is the selection of optimal antigen targets, which should show natural, high frequent and tumor-exclusive presentation on the cell surface of malignant cells and are recognized by patients T cells. Several studies have suggested neoepitopes arising from tumor-specific mutations as central specificities of checkpoint inhibitor induced T-cell responses in solid tumors. However, besides these neoantigens, several groups also described tumor-associated self-peptides that are able to induce peptide-specific T-cell responses and could be used as targets for peptide-based immunotherapy approaches. To identify tumor-associated self- and neoantigens we are using a direct method of HLA-presented peptide isolation and mass spectrometric analysis followed by various T-cell assays to prove the immunogenicity of our newly defined antigen targets. Current project are focusing on the identification of tumor-associated antigens for chronic myeloid leukemia (Wilhelm Sander grant), +CD38- AML progenitor/tumor stem cells and premalignant and early stages of HM including monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma (SMM), myelodysplastic syndrome (MDS), Polycythemia vera and myelofibrosis.

Figure 1: Immunopeptidome-centric workflow used for the identification of tumor-associated HLA ligands in leukemia patients. Com-parative analysis of HLA ligands presented on cells of leukemia patients and healthy individuals by mass spectrometry identifies the most frequently represented leukemia-exclusive antigens. Functional characterization by ELSIPOT assay identifies preexisting T cell responses strictly directed against CLL-associated antigens exclusively in leukemia patients.
Translation of experimental work in clinical peptide vaccination studies for patients with hematological malignancies

The feasibility of translating our experimental data in clinical trials is demonstrated by our ongoing multi center patient-individualized peptide vaccination study for CLL patients iVAC-L-CLL01 (NCT02802943). All clinical studies are developed in close collaboration with Prof. Rammensee and Prof Stevanovic (Department of Immunology, Tübingen) and Prof. Salih (KKE Translational Immunology, Tübingen). The following study concepts are planned for the next years:

  • Phase I peptide vaccination study with a new synthetic lipopeptide adjuvant in relapsed CLL patitients
  • Phase II peptide vaccination study for AML patients after allogeneic stem cell transplantation
  • Phase II multi center randomized peptide vaccination study for CML patients after stopping TKI treatment


Figure 2: Schematic presentation of the analysis on tumor cell immunopeptidome alterations under cancer drug treatment (A, B) and of the identification of treatment-associated/exclusive HLA ligands (C, D)
Influence of cancer treatment on the immunopeptidome of hematological malignancies

The aim of these projects is to identify suitable adjuvants and immunomodulatory drugs for combination with peptide-based immunotherapy, which ideally reinforce peptide-specific T-cell responses and do not affect the immunopeptidome, i.e. robust presentation of peptide targets. Furthermore, some anti-cancer drugs might even induce novel treatment-associated peptides, which may represent interesting candidates for the improvement of immune control in HM. We are using an established

in vitro

treatment model to longitudinally and semi-quantitatively map the impact of different drugs on the immunopeptidome of HM using primary patient samples and cell lines. Cancer drugs of interest are for example demethylating agents, immune checkpoint inhibitors, HDAC inhibitors, TKIs and JAK2 inhibitors.


Further more we analyze the positive and negative effects of standard anti-cancer drugs (e.g. TKIs, demethylating agents, JAK2 inhibitors, etc.) as well as potential adjuvants (imiquimod, synthetic lipopeptides) and immunomodulatory drugs (lenalidomide, checkpoint inhibitors) on T-cell proliferation and function.

Figure 3: Treatment schedule iVAC-L-CLL01 study; MRD, minimal residual disease; PV, peptide vaccination.

Scholarships, awards, qualifications

Since 2015 Member of the German Society of Hematology and Medical Oncology
2007 - 2008 Member of the graduate schoo 794 (dissertation fund) "cellular mechanisms of immune associated processes", University of Tübingen
2011 Dissertation Award of the Eberhard Karls Universität Tübingen
2011 Ludolf Krehl Dissertation Award of the Süddeutschen Gesellschaft für Innere Medizin
2012 Abstract Achievement Award American Society of Hematology
2013 Abstract Achievement Award American Society of Hematology
2014 Abstract Achievement Award American Society of Hematology
2015 Poster Price DGHO Basel
2015 Württembergischer Krebspreis, Nachwuchspreis
2016 Young Investigator Award DGHO Leipzig
2017 Poster Price of the University of Tübingen, Forschungskolloquium


Funding

  • Jose Carreras Leukämiestiftung
  • DFG grant (DFG STI 704/1-1)
  • Wilhelm Sander-Stiftung grant (Nr. 2016.177.1)
  • TÜFF Habilitandinnen Stipendium
  • Württembergischer Krebspreis
  • IZKF Nachwuchsgruppe, University of Tübingen
  • AKF Program University of Tübingen
  • IIT Anreizprogramm University of Tübingen


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