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Immunotherapy

PD Dr. Juliane Sarah Walz, geb.Stickel

++49-711-8101 2633

Major Projects
  • Project 1: Identification and characterization of tumor-associated antigens
  • Project 2: Influence of cancer treatment on the immunopeptidome of hematological malignancies
  • Project 3: Translation of experimental work in clinical peptide vaccination studies for patients with hematological malignancies
  • Project 4: T-cell immunity in COVID-19

  • >>more on seperate subpage "Major Projects"
     
Selected References
  • Nelde A, Bilich T, Heitmann JS, Maringer Y, Salih HR, Roerden M, Lübke M, Bauer J, Rieth J, Wacker M, Peter A, Hörber S, Traenkle B, Kaiser PD, Rothbauer U, Becker M, Junker D, Krause G, Strengert S, Schneiderhan-Marra N, Templin MF, Joos TO, Kowalewski DJ, Stos-Zweifel V, Fehr M, Rabsteyn A, Mirakaj V, Karbach J, Jäger E, Graf M, Gruber LC, Rachfalski D, Preuß B, Hagelstein I, Märklin M, Bakchoul T, Gouttefangeas C, Kohlbacher O, Klein R, Stevanović S, Rammensee HG, Walz JS (2020). SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T-cell recognition. Nature Immunology 2020 [in press].
  • Heinrich B, Brown ZJ, Diggs LP, Vormehr M, Ma C, Subramanyam V, Rosato U, Ruf, B, Walz JS, McVey JC, Wabitsch SF, Fu Q, Yu SJ, Zhang Q, Lai, CW, Sahin U, Greten TF (2020). Steatohepatitis impairs T cell-directed immunotherapies against liver tumors in mice. Gastroenterology 2020 [in press].
  • Bilich T*, Nelde A*, Bichmann L, Roerden M, Salih HR, Kowalewski DJ, Schuster H, Tsou CC, Marcu A, Neidert MC, Lübke M, Rieth J, Schemionek M, Brümmendorf TH, Vucinic V, Niederwieser D, Bauer J, Märklin M, Peper JK, Klein R, Kohlbacher O, Kanz L, Rammensee HG, Stevanović S, Walz JS (2018). The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy. Blood. 2019 Feb 7;133(6):550-565.
  • Neidert MC, Kowalewski DJ, Silginer M, Kapolou K, Backert L, Peper JK Marcu A, Freudenmann LK, Wang S, Walz JS, Wolpert F, Rammensee HG, Henschler R, Lamszus K, Westphal M, Roth P, Regli L, Stevanovic S, Weller M, Eisele, G (2018). The natural HLA ligandome of glioblastoma stem-like cells: Antigen discovery for T cell based immunotherapy. Acta Neuropathol. 2018 Jun;135(6):923-938
  • Liu X, Pichulik T, Wolz OO, Dang TM, Stutz A, Page C, Garcia MD, Kraus H, Dickhöfer S, Daiber E, Münzenmayer L, Wahl S, Rieber N, Kümmerle-Deschner J, Yazdi A, Franz-Wachtel M, Macek B, Radsak M, Vogel S, Schulte B, Walz JS, Hartl D, Latz E, Stilgenbauer S, Grimbacher B, Miller L, Brunner C, Wolz C, Weber AN (2017). Human NLRP3 inflammasome activity is regulated by and potentially targetable via BTK. Allergy and Clinical Immunology. 2017 Oct;140(4):1054-1067.e10.

Curriculum Vitae Juliane S. Walz, PhD

Affiliation
Head of AG Immunotherapy Robert Bosch Cancer Centre, Stuttgart

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology
Auerbachstrasse 112
70376 Stuttgart Germany
phone: ++49-711-8101 2633
fax: ++49-711-859295
email: Juliane.walz@ikp-stuttgart.de
Education and Professional Career
  Academic education
2004 - 2010 Medical school, Eberhard Karls University Tübingen
September 2006: first part of medical examination
(grade very good, 1,5)
November 2010: second part of medical examination
(grade very good, 1,5)
2007-2011 MD work at the Department of Immunology, University Tübingen „Qualitative und quantitative Analyse und Vergleich von Tumorantigenen und HLA-Klasse I-Liganden in Primärtumoren und Metastasen des Nierenzellkarzinoms“.
Member of the graduate school SFB 794 „Zellbiologische Mechanismen immunassoziierter Prozesse“.
04/2011 Medical dissertation, summa cum laude
05/2018 Habilitation (internal medicine) at the Medical Faculty, Eberhard Karls University Tübingen
  Professional career
2011-2017 Residency at the University Hospital Tübingen, Medical Department II
Since 01/2012 Research group leader Department of Immunology, University Tübingen „Peptide-based immunotherapy“
05/2017 Specialist for internal medicine and hematology and oncology at the University Hospital Tübingen, Medical Department II
04-08/2019 Research scholarship, National Institute of Health (NIH), lab of Prof. Tim Greten, Bethesda, USA
09/2019-8/2020 Senior physician CCU Translational Immunology/Department of Hematology and Oncology
Since 7/2020 Head of the “Wirkstoffpeptidlabor”, Department of Immunology, University of Tübingen
Since 09/2020 Head of AG Immunotherapy Robert Bosch Cancer Centre, Stuttgart and Senior physician CCU Translational Immunology, University Hospital Tübingen
Prizes and awards
2011 Dissertation award of the Eberhard Karls University Tübingen
2011 „Ludolf Krehl 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 Award“ DGHO Basel
2015 „Württembergischer Krebspreis“, junior award
2016 Young Investigator Award DGHO Leipzig
2017 „Poster Award“ of the University Tübingen, research colloquium
2018 „Poster Award“ DGHO Wien
2020 „Poster Award“ of the University Tübingen, research colloquium
Patents
  • Novel immunotherapy against several tumors of the blood, such as acute myeloid leukemia (AML); Application number: PCT/EP2015/060168
  • Novel immunotherapy against several tumors of the blood, in particular chronic lymphoid leukemia (CLL); Application number: PCT/EP2015/063566
  • Novel cell epitopes and combination of cell epitopes for use in the immunotherapy of myeloma and other cancers; Application number: PCT/EP2016/064317
  • Peptides and combination of peptides for use in immunotherapy against leukemias and other cancers: Application number: PCT/EP2018/059114
  • Peptides and combination thereof for use in the immunotherapy against cancers; Application number: PCT/EP2018/059109
  • CoVac-1 peptide cocktail; Application number: PCT/EP 20 190 070.1
  • SARS-CoV-2 CD8+ und CD4+ T cell epitopes; Application number: PCT/EP 20 169 047.6

Identification and characterization of tumor-associated antigens

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 malignant tumors. 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, CD34+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. Comparative 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.

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 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)

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

T-cell immunity in COVID-19

T-cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for development of vaccines, identification of exact viral T cell epitopes is fundamental. In these projects we aim to identify and characterize dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR T cell epitopes in COVID-19 convalescent and unexposed individuals. This enables the diagnostic and long-term monitoring of T-cell immunity in convalescents after SARS-CoV-2 infection but also the detection of preexisting cross-reactive SARS-CoV-2 T-cell responses in unexposed individuals.

Furthermore, we are currently translating the preclinical results of these project in a phase I peptide vaccination trial aiming to induce protective SARS-CoV-2 T-cell immunity to combat COVID-19 (NCT04546841)
 
Figure 4. Characterization of dominate and subdominant SARS-CoV-2 T-cell epitopes in COVID-19 convalescents and unexposed donors.