Getting a cancer patient's immune system to "focus" on the tumor cells in the body and fight the life-threatening disease - this works very well in many cases with CAR-T cells in patients with certain leukaemias (blood cancers) and lymphomas (lymph gland cancers). This means that the cancer disappears or at least does not develop to such an extent that the patients die.
CAR-T stands for "chimeric antigen receptor in T cells". T-cells are cells of the immune system. The cancer cells use various molecular tricks to evade their "normal" attempts to attack. This means that the immune cells no longer recognize their opponents, the cancer cells, at all. As part of the therapy, T cells are taken from the patients and genetically engineered to produce a specific protein (CD19) on their surface. When the CAR-T cells are introduced into the patient's body, CD19 ensures that the CAR-T cells recognize the cancer cells and bind to them precisely. The cancer cells then die.
However, solid tumors such as colon, breast, prostate or lung cancer have developed mechanisms that render the CAR-T cells ineffective. "However, we are gaining a better understanding of the molecular mechanisms behind this," says Prof. Dr. Sebastian Kobold, Director of the Department of Clinical Pharmacology. His team has shown, for example, that prostaglandin E2 (PGE2) suppresses the function of T cells in the microenvironment by binding to special receptors on the surface of the T cells.
The Munich researchers and their colleagues have now genetically engineered therapeutic CAR T cells. The CARs are then no longer able to produce these special receptors. As a result, PGE2 can no longer bind to the CAR-T cells and exert its immunosuppressive effect. This was demonstrated by the fact that the CAR-T cells kept the tumors in check in mice with breast or pancreatic cancer. These CAR-T cells also proved to be highly effective in tumor samples from patients with pancreatic and colon cancer as well as neuroendocrine tumors.
"Our new approach will soon be tested in clinical trials," says Dr. Janina Dörr, first author of the study and researcher in the Immunopharmacology working group at the Department of Clinical Pharmacology. But initially not with patients with solid tumors, but with lymphoma patients. Here, too, only just under half of those treated have benefited from CAR-T therapy to date. "According to our findings, it is quite possible that therapy with PGE2 switched off is significantly more successful," explains Kobold. If this is the case, a study with patients with solid tumors could follow if the necessary funding is available.
