Vaccination of cancer patients with dendritic cells electroporated with mRNA encoding the wilms' tumor 1 protein (WT1): correlation of clinical effect and overall survival with T-cell response

Abstract

Background & Aim Dendritic cells (DC) have the capacity to induce potent tumor antigen-specific T-cell immunity. We have completed vaccination in the adjuvant setting in 77 cancer patients (acute myeloid leukemia (AML, n=30), metastatic breast cancer (MBC, n=12), glioblastoma multiforme (GBM, n=13), malignant pleural mesothelioma (MPM, n=10) and other solid tumors (n=12)) with autologous DC electroporated with mRNA encoding the nearly universal tumor-associated antigen Wilms’ tumor 1 protein (WT1). Methods, Results & Conclusion WT1-targeted DC vaccination was feasible and safe in all patients. The majority of the patients showed a positive delayed type hypersensitivity (DTH) response to the vaccine. Objective clinical responses were observed among all tumor types, including complete (CR) and/or molecular remissions or stable disease (SD) in the AML group, partial responses (PR) and SD in the GBM group and SD in the MBC and MPM groups. In AML patients in first CR, median overall survival (OS) calculated from time of diagnosis was 56.1 months (mo). Median OS from time of diagnosis of metastasis was 41.9 mo in MBC, 43.7 mo from diagnosis in GBM and 35.7 mo from start of therapy in MPM; this compares favorably to numbers reported in the literature, respectively 24.8 mo, 14.7 mo and 22 mo. In AML, long-term OS was correlated with WT1-specific polyfunctional CD8+ T-cells in the DTH reaction sites and long-term CR with polyepitope WT1-specific tetramer+ CD8+ T-lymphocytes. In solid tumors, PR or SD was correlated with interferon (IFN)-gamma+ and/or tumor necrosis factor (TNF)-alpha+ WT1-specific CD4+ and/or CD8+ T-cells; increased OS in the GBM+MPM cohorts was correlated with IFN-gamma+ WT1-specific CD4+ T-lymphocytes. In conclusion, WT1-targeted DC vaccination is feasible, safe and immunogenic, and displays relevant anti-tumor activity in patients with hematological and solid malignancies. Most importantly, this treatment modality can confer a significant survival benefit to the patients.