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