Immunotherapy of Rhabdomyosarcoma
Rhabdomyosarcoma is the malignant soft tissue carcinoma in children with highest incidence. It can be distinguished by its morphology, the immune phenotype and especially the detection/exclusion of repeatedly occurring translocations (t(1;13) and t(2;13)). Thus, it can be classified in the following types:
- Alveolar
- Embryonal
- Pleomorphic RMS
In spite of aggressive chemotherapies using high doses, the mean 5-year survival time is 30-60%. The 5 year survival time of alveolar RMS with the translocation (t2;13) as well as metastatic RMS and RMS in children >10 years in age is only 5-10%.
RMS cells are characterized by the expression of the fetal Acertylcholine receptor (fAChR), which in adults is only expressed in single fibers of external eye muscles and in non-enervated myoid cells of the thymus. During normal muscle development, the innervation of all other tissues leads to an exchange of the fetal gamma-subunit for the alpha-subunit prevalent in the adult form of the AChR. Thus, the fAChR expressed by RMS cells represents a suitable target for a specific, antibody-based therapy.
The task of the EMI group
In collaboration with Prof. Gattenlöhner (Institute for Pathology, University Hospital Gießen and Marburg, location Gießen), we work with a human scFv targeting the fAChR (scFv35). scFv35 is fused with the deletion mutant of the bacterial Exotoxin A from Pseudomonas aeruginosa. We already characterized the immunotoxin in vitro in our group and tested it in preliminary murine in vivo experiments for the therapy of RMS. We could show that scFv35-ETA’ leads to a decelerated tumor growth in comparison to the control group.
Because of the immunogenicity of bacterial toxins, we like to use human enzymes (like the ribonuclease angiogenin or the protease granzyme B) instead of ETA’ as effector domains and evaluate these in in vivo models in comparison to scFv35-ETA’ as standard.
The low expression of the fAChR on RMS cells limits the evaluation of new, RMS-specific therapeutics. It is known that fAChR expression is increased after chemotherapy in in vitro as well as in vivo experiments. The increase of receptor expression after incubation of RMS cells with several agents already described in literature is another aim of the project. Cells with enhanced fAChR expression will be subsequently used in mouse models for evaluation of the already mentioned new therapeutics.
