Development of Cellular Therapeutics
Adoptive immunotherapy based on the transfer of T cells modified with CARs has recently been proven in clinical studies to mediate impressive regression and even cure of tumours. Thus, the approach is currently one of the most promising forms of cancer immunotherapy. Our prime goal is to establish new immunotherapeutic options based on CAR-modified T cells for several paediatric malignancies, such as the different types of sarcomas, glioma and certain types of leukaemia. Additionally, we hypothesize that the CAR-approach could also be adapted for the treatment of infections with Cytomegalovirus (CMV), which is still a major complication in transplant patients.
Targeting Ewing sarcoma by T cells expressing a NKG2D-based CAR Ewing sarcoma is a rapidly disseminating and highly malignant bone cancer in children and young adults. Although survival rates have considerably improved for localized disease, patients with metastatic and recurrent disease urgently require improved therapeutic options. Ewing sarcoma and other paediatric highly malignant tumours are characterized by the expression of NKG2D-ligands, which are absent on most normal tissues. We have therefore generated a CAR based on the ectodomain of NKG2D (chNKG2D). T cells equipped with this receptor can recognize and kill Ewing sarcoma cells with high efficiency. Our data strongly suggest further pursuing the chNKG2D-based approach to target Ewing sarcoma and possibly other cancers. We therefore plan to further develop the approach in a preclinical model for allowing transfer to clinical application. Additionally, we want to pursue the CAR- approach by developing novel molecular tools for improving safety and efficacy of the manipulated T cells.
Retargeting T cells to viral glycoproteins for therapy of CMV infections Reactivation of CMV in immunocompromised patients can still cause life-threatening complications. An attractive treatment strategy is the application of virus-specific cytotoxic T cells, which can be enriched from the blood of CMV positive donors. This strategy has been successfully established in our institute by the group of Clinical Cell Biology and FACS core unit and is now being tested clinically. However, this strategy is not applicable in the high risk subgroup of stem cell transplant patients with CMV sero-negative donors. Therefore we developed, within an ongoing international collaboration project, a complementary approach based on CARs targeting the CMV glycoprotein B. These CARs trigger specific T cell effector functions like degranulation and release of inhibitory cytokines in response to CMV-infected target cells. In ongoing experiments we examine differentially activated T cells and NK cells engaged with the CAR for their potential to lyse CMV infected cells to identify the most suitable vehicles for CMV directed immunotherapy.
- Lehner M., G. Götz, J. Proff, N. Schaft, J. Dörrie, F. Full, A. Ensser, Y.A. Muller, A. Cerwenka, H. Abken, O. Parolini, P.F. Ambros, H. Kovar, W. Holter. Redirecting T cells to Ewing´s sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection. PLoS ONE 2012. 7: e31210.
- Lehner M., B. Kellert, J. Proff, MA. Schmid, P. Diessenbacher, A. Ensser, J. Dörrie, N. Schaft, M. Leverkus, E. Kämpgen, W. Holter. Autocrine TNF is critical for the survival of human dendritic cells by regulating BAK, BCL-2, and FLIPL. J.Immunol. 2012. 188: 4810-4818.
- Full F., M. Lehner, V. Thonn, G. Götz, B. Scholz, KB. Kaufmann, M. Mach, H. Abken, W. Holter, A Ensser. T cells engineered with a cytomegalovirus-specific chimeric immunoreceptor. J.Virol. 2010. 84: 4083-4088.
- Holter W., G. Ressmann, N. Grois, M. Lehner, O. Parolini, H. Gadner. Normal monocyte-derived dendritic cell function in patients with Langerhans-cell-histiocytosis. Med.Pediatr.Oncol. 2002. 39: 181-186.
- Lehner M., T. Felzmann, K. Clodi, W. Holter. Type I interferons in combination with bacterial stimuli induce apoptosis of monocyte-derived dendritic cells. Blood 2001. 98: 736-742.