Engineering von ROR1-spezifischen CD8+ T-Zellen zur adoptiven Immuntherapie bei chronischer lymphatischer Leukämie
Zusammenfassung der Projektergebnisse
There is now convincing evidence from clinical studies that the use of engineered T cells that are genetically modified to express synthetic tumor-targeting receptors (chimeric antigen receptors: CARs) has the potential to induce durable remissions in patients with advanced malignancies. Our group has focused on developing CAR T cell therapy directed against the ROR1-molecule which is uniformly present on the surface of B-cell chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma and a subset of B-cell acute lymphoblastic leukemia, and as recent studies have shown also several types of solid tumors including breast cancer and renal cell cancer. Our group was the first to construct a ROR1- specific CAR and demonstrate that T cells expressing this ROR1-CAR can specifically eliminate ROR1+ tumor cells in the test tube. The support of the DFG has allowed us to construct several additional ROR1-CARs that are optimized for recognition of tumor cells and we have now been able to show that T cells expressing these optimized ROR1-CARs confer even better anti-tumor responses against ROR1+ tumor cells in the test tube and also in a small animal tumor model. An important requirement for the clinical translation of immunotherapy with ROR1-CAR modified T cells is demonstrating that such an approach will be safe. During the grant period we have made major progress in this aim and performed toxicology studies in pre-clinical models that indicate that targeting ROR1 on tumor cells will be safe and not be associated with significant damage to normal tissues. The project has allowed us to pursue our efforts of developing a safe and effective treatment for patients with ROR1+ hematologic malignancies and solid tumors and perform critical experiments to prepare a clinical trial in the near future.
Projektbezogene Publikationen (Auswahl)
- 2010. The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1- specific chimeric antigen receptor. Blood 116:4532-4541
Hudecek, M., Schmitt, T.M., Baskar, S., Lupo-Stanghellini, M.T., Nishida, T., Yamamoto, T.N., Bleakley, M., Turtle, C.J., Chang, W.C., Greisman, H.A., Jensen, M.C., Rader, C., Riddell, S.R.
