Development of a new immunotherapeutic approach for the treatment of pancreatic adenocarcinoma by combining tumor-specific CAR-T cells with tumour-persistent immunostimulating bacteria.

• Applicant: Dr. Markus Chmielewski
• Subject Area: Gastroenterology ; Immunology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 435414693

The diagnosis of pancreatic carcinoma means for most of the affected persons no possibility of a cure and an extremely unfavorable relative five-year survival rate. The curative possibilities with the help of conventional forms of therapy are often limited by the advanced stage of the disease at the time of diagnosis. Therefore, it is of great social importance to develop new treatment options against this malignant tumor disease. Adoptive T-cell therapy is a promising, targeted strategy in the treatment of tumor diseases. The expression of a chimeric antigen receptor (CAR) gives T cells new specificity against tumor-associated antigens (TAA) expressed on the surface of tumor cells. The binding of such a CAR leads to T-cell-mediated lysis of the affected tumor cells. While CAR T-cell mediated immunotherapy has enjoyed great success in the treatment of malignant hematological diseases, the hopes raised in it have not yet been fulfilled in the treatment of solid tumors. This research aims to extend CAR T-cell therapy to the treatment of solid tumors, in particular pancreatic cancer. This goal is to be achieved by developing a new combination therapy of CAR T cells and immunomodulating bacteria. Genetically modified gram-negative E. coli bacteria of the strain Nissle1917 with inducible expression of an immune-activating cytokine on the surface, will be administered orally to pancreas tumor-bearing, immunocompetent mice. As a rule, such bacteria in healthy tissue will be completely eliminated by the endogenous immune system. However, the pancreatic tumor represents an immune-privileged area where such bacteria can survive and persist in the long term. The aim is to actively exploit this phenomenon through the inducible expression of a proinflammatory cytokine limited to tumor tissue in order to modulate the tumor stroma permanently and thus recruit CAR T cells as well as endogenous immune cells, in particular tumor-associated macrophages (TAMs), natural killer cells (NK), NK T cells (NKT) for the elimination of the tumor. The testing of the following candidates is intended: TNF-ɑ, IFN-γ, IL-18, IL-21 and GM-CSF. It is planned that inducible cytokine expression on the surface of tumor-persistent bacteria will establish an acute inflammation in the area of the pancreatic tumor. In the second part of this combination therapy, tumor-specific CAR T cells will be injected intravenously to completely eliminate the tumors favored by bacterial-mediated immune modulation of the tumor microenvironment. We expect from this combination therapy that the often incurable pancreatic tumor disease will receive a new immunotherapeutic option with the prospect of cure.

• DFG Programme: Research Grants