Wspólnotowy Serwis Informacyjny Badan i Rozwoju - CORDIS

Final Activity Report Summary - ATTACC (Dendritic cell based cancer immunotherapy targeting the tumor stroma)

The main goal of this project was to improve patient care in patients with Adrenocortical carcinoma (ACC), which is a rare, but highly malignant tumour. To achieve this long-term goal, we aimed at establishing an immunotherapy against this disease.

However, the propensity of tumour cells to escape immune elimination could defeat the long-term benefits of effective immunotherapeutic protocols. The immunological targeting of tumour stroma, i.e. 'normal' cells that surround tumour cells, and cells that suppress the immune system of the patient could significantly reduce tumours' ability to evade immune elimination.

In the main part of our project, which was published in Clinical Cancer Research 2005, 11:5566 and Cancer Research 2005, 65:11156, we established a method to screen for human tumour stromal products that could serve as targets for cancer immunotherapy. Using cell culture assays we demonstrated that an immune response against a protein called Fibroblast activation protein (FAP) could be consistently generated, however not against several other candidates. By modifying FAP through fusing a certain targeting signal from another gene, namely LAMP-1, we could significantly enhance FAP immunogenicity. Via mouse experiments we demonstrated that vaccination against FAP using dendritic cells inhibited tumour growth in tumour-bearing mice comparable to that of vaccination against tumour cells. Remarkably, this method was not only successful against a single type of cancer, but was also successful against melanoma, breast cancer and lymphoma. Again, the modified FAP-LAMP product enhanced the effects. Apart from a small delay in wound healing, no side effects were detected.

In a second project, published in Cancer Research 2007, 67:371, we tried to improve our immunotherapy approach through vaccination against regulatory T-cells. These cells were supposed to diminish an effective immune response against tumour via suppression of tumour-specific immune cells. In a mouse model, we could demonstrate that vaccination against forkhead box P3 (FOXP3) using dendritic cells suppressed the regulatory T-cells and potentiated a tumour-specific vaccination in these tumour-bearing mice.

Furthermore, in an independent third project, published in Journal of Clinical Endocrinology and Metabolism 2006, 91:4501, we investigated the role of adjuvant radiotherapy of the tumour bed in patients after ACC surgery. The data of this large series of ACC patients treated with adjuvant tumour bed irradiation indicated that radiotherapy was effective in reducing the high rate of local recurrence in ACC.

In summary, our studies provided evidence that a co-vaccination against the tumour stroma product FAP and FOXP3, a marker of regulatory T-cells, was a promising approach for a new therapy against different malignancies. In addition, through our clinical study in ACC patients we could demonstrate that adjuvant radiotherapy was an effective treatment to prevent local recurrence in these patients.

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