RNA Based Cancer Vaccines - Clinical Trials in Patients with Prostate Cancer and Malignant Melanoma.

Anti-tumour vaccines targeting the entire tumour antigen repertoire represent an attractive immunotherapeutic approach. This repertoire is present in the total mRNA isolated from the tumour. The mRNA from each cancer patient may be amplified and thus overcome the problem of limitation of material that has hampered the development of individualized vaccines. We have developed immuno-gene-therapy for malignant melanoma and prostate cancer. Monocyte-derived dendritic dells are transfected with autologous melanoma-mRNA or mRNA from three prostate cancer cell lines (DU-145, LN-CaP and PC-3). The vaccines may generate T cell responses against a broad repertoire of tumor-associated epitopes, and the melanoma approach moreover target patient-specific tumor antigens. Effective protocols were established for mRNA-transfection by square wave electroporation and for generation of clinical grade dendritic cells. A full scale preclinical evaluation demonstrated in vitro T cell responses in 6/6 advanced melanoma patients. The responses were specific to antigens encoded by the transfected tumor-mRNA. Recently, we have conducted two phase I/II trials, in advanced malignant melanoma and androgen-resistant prostate cancer. Successful vaccine preparations were obtained for all 41 patients elected. No serious adverse effects were observed. Specific T cell responses (T cell proliferation and/or IFNγ ELISPOT) were demonstrated in 9/19 evaluable melanoma patients and in 12/19 prostate cancer patients. The response rates were higher for patients receiving intradermal vaccination, compared to intranodal injection. Thirteen prostate cancer patients developed a decrease in log-slope PSA. The PSA-response was significantly related to the T cell response (p=0,002). We conclude that the tumour mRNA based DC-vaccine is feasible and safe, and that T cell responses are elicited in about 50% of patients. In the next generation clinical protocols, patients will undergo Treg depletion by chemotherapy (Temozolomide) prior to DC vaccination. Subsequently, T cells will be expanded ex vivo using the Dynabeads Clin Ex Vivo system before re-infusion into the patients.