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Modulation of specific immunity upon anti-cancer therapy

English title Modulation of specific immunity upon anti-cancer therapy
Applicant Zippelius Alfred
Number 123489
Funding scheme SNSF Professorships
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.01.2010 - 31.12.2013
Approved amount 1'514'599.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Clinical Cancer Research

Keywords (10)

cancer; immunity; T cells; chemotherapy; tumor microenvironment; anti-tumor immunity; T cell response; immunotherapy; immuno-modulation; tumor antigen

Lay Summary (English)

Lead
Lay summary
Though conventional cytotoxic anti-cancer therapies may blunt the immune system, evidence has accumulated that those therapies support anti-tumor immunity under certain circumstances. In preclinical tumor models, mechanisms including immuno-modulatory effects and immunogenic cancer cell death upon treatment have been proposed. Clinical observations further support a concept that cytotoxic therapies enhance the efficacy of immunotherapy. It is the aim of this project to decipher the potential immunogenicity and the precise immuno-regulatory pathways of those therapies as well as to define possible synergistic effects with immunotherapy. To this end, we will assess anti-tumor immunity in a conditional tumor model and in cancer patients upon anti-tumor therapy. The research is therefore dedicated to improve our understanding of anti-tumor immunity, in particular upon treatment with novel anti-cancer therapies. This will pave the way for rationally designed clinical trials that aim at dissecting therapeutic synergies of cytotoxic treatment modalities combining those agents with novel immuno-based targeted therapies.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells.
Müller P, Martin K, Theurich S, Schreiner S, Savic S, Terszowski G, Lardinois D, Heinzelmann-Schwarz VA, Schlaak M, Kvasnicka HM, Spagnoli G, Dirnhofer S, Speiser DE, von Bergwelt-Baildon M, Zippelius A (2014), Microtubule-depolymerizing agents used in antibody-drug conjugates induce antitumor immunity by stimulation of dendritic cells., in Cancer Immunol Res., 2(8), 741-755.
The microtubule-depolymerizing agent ansamitocin P3 programs dendritic cells toward enhanced anti-tumor immunity.
Martin K, Müller P, Schreiner J, Savic S, Lardinois D, Heinzelmann-Schwarz VA, Thommen DS, Zippelius A (2014), The microtubule-depolymerizing agent ansamitocin P3 programs dendritic cells toward enhanced anti-tumor immunity., in Cancer Immunol Immunother., 63(9), 925-938.
Memory and effector CD8 T-cell responses after nanoparticle vaccination of melanoma patients.
Speiser D, Schwarz K, Baumgaertner P, Manolova V, Devevre E, Sterry W, Walden P, Zippelius A, Conzett KB, Senti G, Voelter V, Cerottini JP, Guggisberg D, Willers J, Geldhof C, Romero P, Kündig T, Knuth A, Dummer R, Trefzer U, Bachmann MF (2010), Memory and effector CD8 T-cell responses after nanoparticle vaccination of melanoma patients., in J Immunother, 33(8), 848-858.
Tumor-specific crosslinking of GITR as costimulation for immunotherapy.
Burckhart T, Thiel M, Nishikawa H, Wüest T, Müller D, Zippelius A, Ritter G, Old L, Shiku H, Renner C (2010), Tumor-specific crosslinking of GITR as costimulation for immunotherapy., in J Immunother, 33(9), 925-934.

Collaboration

Group / person Country
Types of collaboration
Roche Glycart Switzerland (Europe)
- Industry/business/other use-inspired collaboration
Seattle Genetics United States of America (North America)
- Industry/business/other use-inspired collaboration
Actelion Switzerland (Europe)
- Industry/business/other use-inspired collaboration
Prof. Sai Reddy, D-BSSE, ETH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
German Hodgkin Group Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
CIMT Meeting Talk given at a conference Microtubule-depolymerizing agents used in antibody-drug-conjugates induce anti-tumor immunity by stimulation of dendritic cells 12.05.2014 Mainz, Germany Müller Philipp; Zippelius Alfred;
Keystone Meeting Inflammation, Infection and Cancer Poster Microtubule-depolymerizing agents used in antibody-drug-conjugates induce anti-tumor immunity by stimulation of dendritic cells 03.02.2014 Whistler, United States of America Zippelius Alfred; Müller Philipp;
DGHO Annual Meeting Talk given at a conference Immuno-oncology 18.10.2013 Wien, Austria Zippelius Alfred;
Basel Onco-Day Talk given at a conference Exploring the immuno-modulatory mechanisms of the tyrosine kinase inhibiter axitinib in tumor-bearing hosts 11.10.2012 Basel, Switzerland Müller Philipp; Zippelius Alfred;
Meeting European Cancer Center Talk given at a conference The tumor-specific immune response significantly contributes to the anti-cancer effect of dolastatin derivatives 04.05.2012 Freiburg/Deutschland, Germany Zippelius Alfred; Martin Kea;
Research Day Department Biomedicine - Evaluation of the International Advisory Board Talk given at a conference Harnessing the immune system to treat cancer from mouse models to patients and vice versa 19.01.2012 Basel, Switzerland Zippelius Alfred;
Meeting European Cancer Center Talk given at a conference Modulation of specific immunity upon anti-tumor therapy: blockade of indoleamine-2,3 dioxygenase to potentiate cancer chemotherapy. 20.05.2011 Basel, Switzerland Zippelius Alfred;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Basler Krebsliga German-speaking Switzerland 2013
Talks/events/exhibitions Vortrag Jahrestagung deutsche/österreichische/schweizerische Gesellschaft für Pneumologie International 2013
Talks/events/exhibitions Basel Translational Medicine Hub Seminar German-speaking Switzerland 2012
Talks/events/exhibitions Tag der Forschung, Universität Basel German-speaking Switzerland 2012

Awards

Title Year
Berufung auf eine Professur 2013
SAKK Research Grant 2013

Abstract

Background: Despite the fact that conventional cytotoxic anti-cancer therapies (i.e. chemotherapy and ionizing radiotherapy) blunt the immune system, evidence has accumulated that those therapies support anti-tumor immunity under certain circumstances. Recent studies mainly performed in preclinical tumor models have proposed mechanisms including immuno-modulatory effects and immunogenic cancer cell death after treatment with those therapies. Importantly, early clinical observations further support a concept that cytotoxic therapies enhance the efficacy of immunotherapy by altering systemic and local mechanisms of tolerance. The potential immunogenicity and the precise immuno-regulatory pathways of cytotoxic therapies as well as possible synergistic effects with immunotherapy reflected by a thorough and extensive assessment of specific anti-tumor immunity upon treatment with selected therapeutics are, however, poorly defined. Aim: It is the aim of this project to investigate how the immune system contributes to the success (or the failure) of cytotoxic anti-cancer therapies. Precisely, we will investigate how chemotherapy and/or radiotherapy modulate the local tumor microenvironment and the tumor antigen specific T cell response. This will contribute to elucidate the underlying mechanisms and to better define the relationship between the immunological “make-up” of an individual tumor and the potential immunogenicity of cytotoxic anti-cancer therapies. This knowledge may enable to develop successful strategies in the clinic for the integration of modalities that combine cytotoxic therapies with immunotherapy. Methods: We propose the following experimental strategies in humans and in mice to tackle these questions:1) We will assess the immune response in the tumor microenvironment in vivo in patients with inoperable squamous head and neck cancer (HNSCC) before and after treatment with chemo- and/or radiotherapy. This will be compared to the analysis of the peripheral blood of those patients to document the magnitude and dynamics of anti-tumor immune responses upon treatment apart from the tumor site. We propose to undertake a comprehensive study of major immuno-modulating immune subsets and of tumor antigen-specific immune responses. In addition, we will investigate local tumor immunity in vitro in primary tumors of patients with HNSCC after treatment with selected chemotherapy drugs and/or radiotherapy utilizing collagen gel matrix-supported organ cultures of tumor biopsies. These experiments are important to carefully study the immunologic effects of each therapeutic modality in humans.2) We will develop a mouse model of spontaneous squamous cancer to dissect those complex immunological mechanisms in an experimentally well-controlled murine setting. Conditional activation of the oncogene K-ras in the skin will result in local tumors of squamous origin; additional expression of the well-defined antigen ovalbumin (OVA) will facilitate immunological read-outs. We will experimentally perturb the tumor microenvironment by chemotherapy and radiotherapy. Furthermore, we will combine cytotoxic therapies with immunotherapy, i.e. vaccination approaches and targeted biologics with proven ability to augment T cell responses, to test our hypothesis that this combination can augment tumor-specific T cell responses. Outlook: The proposed project will contribute to a more accurate understanding of the immuno-modulating capacities of cytotoxic anti-cancer therapies. This will pave the way for rationally designed clinical trials that aim at dissecting therapeutic synergies of treatment modalities combining those agents with novel immuno-based targeted therapies.
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