Abstract

High grade uterine sarcoma and recurrent endometrial carcinoma are aggressive cancers with limited treatment options, resulting in a poor prognosis. In this research we focused in the first place on the detection of a highly immunogenic tumour-associated antigen Wilms’ tumour gene 1 (WT1) in uterine tumours. We were able to reveal its overexpression in the tumour cells of high grade sarcomas and carcinosarcomas . Moreover, patients with WT1 positive tumours had a significantly worse prognosis than patients who were WT1 negative.

For carcinomas, WT1 was present in only a minority of tumour cells, but in the majority of intratumoural blood vessels. Small blood vessels in the normal tissue surrounding the carcinoma were also WT1 positive, suggesting a role for WT1 in angiogenesis. WT1 was hardly expressed or absent in the non-tumour or benign tumoural uterus (myoma, polyp).

The next step was to develop a targeted treatment against WT1. We opted for dendritic cell (DC) based immunotherapy. Nevertheless a basal expression of WT1 in monocytes and in vitro cultured unloaded DC was observed, the electro- poration of in vitro cultured DC with WT1-mRNA resulted in a higher expression of WT1 by the DC. WT1-mRNA loaded DC were used for in vivo stimulations of T cells, resulting in the rise of WT1-specific T cells and a transient molecular response (decrease of CA125) in an end stage endometrial carcinoma patient. No toxic side effects were reported. Future in vivo research, carried out in a phase I clinical trial in our center, will reveal the ability of this new therapy to induce an immunological and possible clinical response in WT1 positive uterine cancer patients.