Analysis of tumormutanome-specific T-cell responses

• Applicant: Dr. Norman Woller
• Subject Area: Gastroenterology ; Immunology
• Term: from 2013 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 239231233

Tumor-specific activated CD8 T cells provide highly specific means for effective treatment of malignant diseases. Most common, cytotoxic immune responses can be elicited by application of dendritic cell vaccines. However, this approach rarely induces significant tumor-remissions due to numerous tumorspecific immune tolerance mechanisms, that induce T cell exhaustion and effectively suppresses immune reactions directed to tumor-tissue. The breakdown of these tumorimmunotolerance mechanisms seems to be crucial to initiate a cytotoxic immune response in a clinical setting. In an earlier study we could demonstrate that a replicative adenovirus injected into tumor tissue allows for highly efficient DC-vaccinations, when the vaccine was applied at the timepoint of oncolytic virus-mediated inflammation of the tumor (oncolysis-assisted DC-vaccination or ODC, respectively). In addition to the strong Th1-polarizing inflammation, an essential mechanism for ODC is effective cross-presentation of tumor antigens in the oncolytic area. In animal tumor models, this therapy is capable to induce potent cytotoxic immune responses that eliminates malignant lung colonies and leads to marked tumor-regression. The aim of this study is to characterize the function and phenotype of ODC-generated tumor-specific T cells. Furthermore we want to investigate the option to establish a novel heterologous ODC sequence in tumor-bearing mice to effectively expand tumorspecific CD8 T cells. For this purpose, the vaccination against tumor-associated antigens will be repetitively applied in the context of ODC-treatment. However, the viral applications will be administered using different virus-species to avoid a predominant antiviral immune responses and premature virus clearance. Therefore, other virus species with established use as oncolytic agents will be tested to allow for identification of viruses that are able to induce fulminant local tumor inflammations like the ODC-prototypic Adenovirus serotype 5, and which are therefore capable to support ODC-treatments. T-cell responses that are raised by these ODC treatments will be functionally characterized. These experiences will be used to optimize the hierarchy of used viruses and the time lag between single ODC applications within a heterologous ODC sequence to generate an optimum of potent tumor-specific CD8 T cells.Therapeutic relevance of ODC-induced T cell responses is then to be validated in a mouse model of cancer with endogenously induced liver tumors. For this purpose, a transposon system with natural murine oncogenes is used to induce hepatic tumors by hydrodynamic injection. Due to the endogenous natural growth these highly tolerogenic tumors meet best the clinical situation and represent an enormous challenge for novel therapeutic strategies. Using this model of hepatic cancer, the therapeutic success of heterologous ODC sequence should be finally investigated.

• DFG Programme: Research Grants