Vaccination with WT1 mRNA-Electroporated Dendritic Cells: Report of Clinical Outcome in 66 Cancer Patients

Tumor recurrence and lack of tumor control are major problems in cancer treatment. In order to control malignant disease, we performed phase I/II dendritic cell (DC) vaccination studies in an adjuvant setting in 30 patients with acute myeloid leukemia (AML) and in 36 patients with solid tumors. Following chemotherapy, the patients underwent leukapheresis; CD14+ monocytes were isolated, cultured into clinical-grade mature DC, electroporated with mRNA encoding the Wilms' tumor protein WT1 and injected intradermally (Van Tendeloo et al. PNAS 2010;107:13824-9). No major DC-related systemic toxicity was observed.

DC vaccination as a post-remission treatment was evaluated in 30 AML patients following chemotherapy; 27 patients were in complete remission (CR) but at very high risk of relapse and 3 in partial remission (PR). WT1 mRNA levels in blood and marrow were followed as a measure of residual disease. Clinical and molecular response, as determined by normalization of WT1 transcript levels in blood and/or marrow, occurred in 8/23 patients who had increased levels of that marker at the start of DC vaccination. Of these 8 responding patients, 5 are still in complete and molecular remission, all of them now more than 5 years after diagnosis and most probably cured; 1 of those 5 patients was in PR following chemotherapy and was brought into complete and molecular remission by the DC vaccination only. There was a possible effect of DC vaccination in 6 additional patients: 3 with stable disease, some of it late; and 3 at high risk of relapse but without increased WT1 mRNA levels before DC vaccination: 1 patient with erythroleukemia and 2 patients with initial leucocytosis >20,000/µL have remained in CR, now at respectively 57, 52 and 45 months post-diagnosis. Overall 8/30 patients have not relapsed yet, with a median follow-up from diagnosis and start of DC vaccination of respectively 70 months (range 45 - 92 months) and 63 months (range 39-90 months). Delayed type hypersensitivity (DTH) testing showed immunoreactivity to the DC vaccine in all patients tested. WT1 epitope tetramer+ CD8+ T-cells were evaluated in 13 HLA-A2+ patients: an increase following DC vaccination in tetramer+ T-cells for at least 2/4 epitopes tested was only observed in patients with long-standing CR.

Ten patients with unresectable, epithelial-type malignant pleural mesothelioma and non-progressive disease after platinum/pemetrexed-based chemotherapy received DC vaccination. Evaluation of response according to RECIST criteria showed 7 patients with stable disease and 3 with progressive disease. DTH testing showed vaccine-elicited immunity in 9/10 patients. Median overall survival (OS) from start of chemotherapy was 32 months; this compares with an OS of 22 months reported in the literature for a similar subgroup of patients treated with chemotherapy only (Hillerdal et al. J Thorac Oncol 2008).

Twenty-six patients with other advanced and pre-treated cancers also underwent DC vaccination (13 with breast cancer (12 with metastatic disease), 5 with glioblastoma multiforme (GBM), 1 with brain stem astrocytoma and 1 each with metastatic melanoma, Ewing sarcoma, esophageal, colon, pancreatic, renal cell and ovarian cancer). Significant DTH responses were recorded in all patients. At a median follow-up from start of DC vaccination of 23.3 months, 8/26 patients (31%) are still alive and median OS was 23.5 months. Evaluation of response showed 3 patients with PR (1 brain stem astrocytoma, 1 GBM and 1 breast cancer) and 1 patient with CR (1 GBM). In the breast cancer patient subgroup, 5/13 patients are still alive (38%) and median OS was 33.5 months after start of DC vaccination; this compares with OS data from the literature of 21.7 months after diagnosis (Kiely et al. J Clin Oncol 2011;29:456-63). In the GBM (n=5) patient subgroup, 1/5 patients is alive in CR 26 months and median OS was 14.7 months after start of DC vaccination; this compares with OS data from the literature of 14.6 months after diagnosis (Stupp et al. N Engl J Med 2005;352:987-96).

In conclusion, WT1-targeted DC vaccination is feasible, safe and immunogenic in cancer patients. In AML, metastatic breast cancer and malignant glioma, there is evidence of objective response. In addition, OS data in solid tumors compare favorably with the best data reported so far for similar cohorts of patients, suggesting that adjuvant WT1/DC-based immunotherapy provides a clinical benefit to these patients.