Experimental and Translational Tumor Immunology

Prof. Dr. Willimsky
 

Development of clinically relevant mouse cancer models and the analysis of the spontaneous and therapy-induced immune response against non-transplanted cancers are central objectives of the Experimental and Translational Tumor Immunology Group.

Cancer cells can be recognized by T cells, the success story of checkpoint inhibitors such as anti-cytotoxic T lymphocytes antigen 4 (CTLA-4) and anti-programmed death 1 (PD-1) has reinforced this notion. Whether destructive or non-destructive spontaneous T cell responses are induced in the autochthonous host is dependent on the inflammatory conditions in which the cancers develop.To this end primary cancer development using conditional cancer antigen expression by Cre/LoxP system in genetically engineered mouse models has shown profound cancer-induced systemic tolerance already at the premalignant stage of sporadic cancers on the one hand and induction of systemic immunity but local antigen specific cytotoxic T cell (CTL) tolerance in virus-induced cancers on the other hand. When CD4 T cells come into play on class I and class II double-positive lymphoma we found some sort of immunosurveillance (Fig.1)

For clinical translation we focus on TCR gene therapy either by adoptive T cell therapy or bispecific antibody formats. This includes the identification of immunogenic target antigens and new methods of therapeutic gene delivery (CRISPR/Cas and mRNA technologies) to fight cancer and viral diseases. Using an unique human TCR transgenic mouse platform (Fig. 2) we generated T cell receptor libraries with naturally optimized affinity against tumor-specific and tumor-associated antigens. Suitable TCRs will be pursued for clinical application. 

Fig. 1: Primary cancer models: To better understand the interaction between T cells and tumor cells and to analyse T cell therapies, mouse models are being used that carry SV40 large T (TAg) as a dormant antigen that can be activated by Cre/LoxP recombination. Fig. 2: Generation of naturally optimized T cell receptors: Upon immunization with human or virus antigens transgenic mice with a diverse human T cell antigen receptor repertoire elicit CD8 or CD4 T cell responses (depending on the HLA-I or HLA-II molecule) allowing the isolation of high-affinity TCRs. © Feriet Tunç

Future projects and goals
In the future spontaneous and therapy-induced T cell response in autochthonous cancer models are investigated in the presence or absence of chronic inflammation, under the influence of different diets (metabolic effects) and in the presence of a natural microbiome (wildling mice).

With the expansion of the TCR generation platform towards mice that harbor various MHC class I and class II molecules we anticipate "practice changing" CD8+/CD4+ combination cancer therapy in the future. 
The establishment of CRISPR/Cas-mediated non-viral gene modification of T cells in closed manufactoring systems will reduce complex GMP structures to a minimum and thus make a more cost-effective T cell therapy clinically applicable more quickly.

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Prof. Dr. Gerald Willimsky

Institute of Immunology

Charité – Universitätsmedizin Berlin /DKFZ

Experimentelle und Translationale Krebsimmunologie / Experimental and Translational Cancer Immunology

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