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Project areas  / Project area C

Project Area C: Immunotherapy

 

This project area represents an ambitious consortium of 7 projects at the forefront of the “next generation” immunotherapy of cancer. Two projects address non-cytotoxic T cell effector mechanisms against experimental tumors and precancerous cells in mice. All other projects are either preparative for new clinical studies in patients or accompanying ongoing therapies.

 

 

  • Project C01 (Röcken/Bauer) studies mechanisms underlying the control of tumor dormancy by CD4+ T cells. During the last period it was found that, surprisingly, Th1 cell cytokines can induce senescence-like cell cycle arrest directly, even in large T antigen (Tag) expressing cancer cells. Tag-specific Th1 cells arrest model cancer in mice through IFN-γ and TNFR1-driven activation of the 16INK4a/Rb senescence pathway. As Rb is non-redundant for cell cycle control the focus of study is now a) the exact signaling pathways by which TNFR1-signaling activates p16INK4a/Rb in concert with IFN-γ and b) the genetic effects of Rb-mediated E2F2 suppression and gene silencing.

 

 

  • Project C03 (Lang/Handgretinger) is at the forefront of an astonishing new clinical development, the use of NK cells and γδ T cells for immunotherapy of leukemic patients after hematopoietic stem cell transplantation by a very elegant approach: These cells can now be retained in the cell preparation containing the hematopoietic stem cells by depleting only the αβ T cells and the B cells, rather than isolating the CD34+ stem cells, as was previously attempted, or by depleting all T and B cells. Thus, a combination of effector cells (NK and γδ T cells, and all other remaining leukocytes) remains in the grafts and is co-transfused together with the stem cells. These cells are unlikely to induce graft versus host disease (GvHD) but may exert anti-leukemic activity. In this application, we plan to carry out concomitant in vitro investigations and to study additional therapeutic possibilities to use NK cells together with ADCC-optimized recombinant antibodies.

 

 

  • Project C05 (Stefan Stevanović and, newly incorporated as a young physician scientist, Jens Bedke) represents, on the one hand, the basic research in immunology for which Tübingen is internationally renowned, namely the biology of MHC peptide presentation, and on the other the major application of HLA ligands for immunotherapy. The final period of this project will complete the identification of T-cell epitopes relevant for renal cell carcinoma (RCC). A comprehensive listing of the entire accessible HLA class I ligandome of RCC will be provided for the most common HLA allotypes. According to our previous experience, about 1% of HLA ligands display tumor-associated features. Tumor-specific HLA ligands will be sought by a combination of next generation sequencing, epitope prediction, and targeted mass spectrometric analysis. We will establish a ready-to-use protocol for patient-individual immunotherapy in RCC to be expandable, in principle at least, to include all other tumor entities. For prostate cancer, in contrast to RCC and most other tumors, differentiation antigens hold great promise for immunotherapy. Therefore, we are following a strategy to evaluate tissue-specific gene expression of the source proteins of HLA ligands. A peptide cocktail useful for vaccination of prostate cancer patients across all HLA frontiers will be attempted. In cooperation with project A15 (N), the exploitability of specific MyD88 mutations for peptide vaccination in lymphoma and leukemia will be explored. Finally, HLA ligandome analysis of tumor stem cells will be attempted. Central to the entire CRC, project C05 will act as a facility for GMP peptides. We recently received the certificate of GMP compliance enabling the use of peptides as active pharmaceutical ingredients in clinical studies. We will continue the application process in order to obtain a full manufacturing authorization for peptide vaccines in order to generate GMP-grade synthetic peptides for application in clinical vaccination studies. Such peptides will fuel novel immunotherapy studies both nationally and internationally.

 

 

  • Project C11: Adoptive transfer of T cells specific for viral antigens is now an established procedure at the Department of Pediatrics using a GMP-compliant protocol with all the required clinical, immunological, technical and regulatory preconditions. Now, we aim at applying adoptive T-cell transfer in the immunotherapy of cancer. Several tumor entities (melanoma, pediatric solid tumors) will be investigated for individual peptides derived from both known immunogenic antigens, as well as individually mutated antigens, which are presented on MHC molecules of autologous tumor cells by ligandome analysis and in silico prediction based on genome sequencing data. These peptides will be used for activating T cells for transfer, whereby our long term goal is adoptive T-cell transfer against individualized selected tumor antigens into a lymphopenic/lymphodepleted host.

 

 

  • Project C12 is again a new project headed by a young physician scientist, Derek Zieker, together with Alfred Königsrainer. Here, we plan to extend our CRC’s central expertise in designing innovative individualized cancer immunotherapy to patients with esophageal adenocarcinoma by selection of mutated and tumor associated antigens by HLA ligand analysis and immunogenicity testing in vitro. In parallel, we will try to identify immune signatures and biomarkers of a large number of tumor samples that have already been collected, in order to learn about patients’ spontaneous immune reactions and their relation to prognosis, in a similar way to that reported for colon cancer by Jerome Galon’s group in Paris. This information will help to optimize the design of a clinical vaccination trial.

 

 

  • Project C13 will analyze the impact of pre-cancerous senescent hepatocyte-stimulated immune surveillance by CD4 T cells during the development of liver cancer will be analyzed. As we detected strong MCP-1 secretion from senescent hepatocytes, we will take advantage of CCR2-/- mice in which the migratory properties of monocytes towards inflammatory sites/MCP-1 are severely impaired. We will apply in vivo imaging technology to study monocyte recruitment, trafficking and differentiation in senescent CCR2-/- mouse livers and we will investigate whether a potentially decreased immune surveillance of senescent hepatocytes in CCR2-/- livers results in an increased liver cancer development. We expect to pave the way for future therapeutic applications harnessing senescence surveillance for the prevention or treatment of cancer.

 

 

  • Project C14 is again a new project led by a highly motivated physician scientist, the pathologist Annette Staebler, together with Hans-Georg Rammensee. Here, the aims are similar to those of project C12: We plan to extend our CRC’s central expertise of designing innovative individualized cancer immunotherapy to patients suffering from ovarian cancer. Based on a long-standing cooperation between the Departments of Immunology, Gynecology, and Pathology, we have already identified several HLA-A2-restricted peptides as promising candidates for inclusion in a multipeptide cocktail for vaccination of patients with ovarian cancers. Now we plan to develop individualized multipeptide vaccination targeting tumor-specific mutations identified by exome and transcriptome sequencing in tumor and normal cells of individual patients which are validated by comparison with the exome sequence of the patient’s blood cells and by mass spectrometric identification of corresponding HLA ligands. In addition, we will study the tumor microenvironment in fresh ovarian carcinoma samples, with particular focus on the occurrence and function of antigen- and mutation-specific regulatory T-cell (Tregs). We shall also use paraffin-embedded tissue in microarray technology to perform in situ analysis of locoregional differences in antigen expression, mutational status and cellular immune response.

 

 

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