Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination

Abstract

Active immunization using tumor antigen-loaded dendritic cells holds promise for the adjuvant treatment of cancer to eradicate or control residual disease, but so far, most dendritic cell trials have been performed in end-stage cancer patients with high tumor loads. Here, in a phase I/II trial, we investigated the effect of autologous dendritic cell vaccination in 10 patients with acute myeloid leukemia (AML). The Wilms' tumor 1 protein (WT1), a nearly universal tumor antigen, was chosen as an immunotherapeutic target because of its established role in leukemogenesis and superior immunogenic characteristics. Two patients in partial remission after chemotherapy were brought into complete remission after intradermal administration of full-length WT1 mRNA-electroporated dendritic cells. In these two patients and three other patients who were in complete remission, the AML-associated tumor marker returned to normal after dendritic cell vaccination, compatible with the induction of molecular remission. Clinical responses were correlated with vaccine-associated increases in WT1-specific CD8 + T cell frequencies, as detected by peptide/HLA-A*0201 tetramer staining, and elevated levels of activated natural killer cells postvaccination. Furthermore, vaccinated patients showed increased levels of WT1-specific IFN-γ-producing CD8 + T cells and features of general immune activation. These data support the further development of vaccination with WT1 mRNA-loaded dendritic cells as a postremission treatment to prevent full relapse in AML patients.cancer vaccine | active specific immunotherapy | phase I clinical trial

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

“…14 In those patients, multiple WT1 CTL epitopes have been recognized as immunogenic (including WT1 [37][38][39][40][41][42][43][44][45] , WT1 [126][127][128][129][130][131][132][133][134] , WT1 [187][188][189][190][191][192][193][194][195] and WT1 [235][236][237][238][239][240][241][242][243] ), demonstrating the excellent in vivo immunostimulatory potential of WT1 (Table 1). 14,72 This is further supported by the capacity to induce WT1-specific CD4 þ helper T-cell immunity in patients with AML through active immunization. 69 High in vivo immunogenicity has also been observed for RHAMM.…”

“…14 This has been demonstrated by the normalization of WT1 transcript levels in peripheral blood and/or bone marrow samples from patients after WT1-targeted immunization, which is indicative of the achievement of a negative minimal residual disease status. 14,72 The most striking demonstration of the immunotherapeutic potential of WT1 is provided by the possibility of obtaining stable and complete remissions in patients with active disease through vaccination. 14,72 Complete remission of AML has also been reported in a number of cases following PR1-targeted active specific immunotherapy, underscoring the clinical value of this peptide for AML immunotherapy.…”

“…14,72 The most striking demonstration of the immunotherapeutic potential of WT1 is provided by the possibility of obtaining stable and complete remissions in patients with active disease through vaccination. 14,72 Complete remission of AML has also been reported in a number of cases following PR1-targeted active specific immunotherapy, underscoring the clinical value of this peptide for AML immunotherapy. 74 The clinical relevance of PR1 is further supported by the observation of a significant disease-free survival advantage and a trend toward improved overall survival in patients with myeloid malignancies developing immunity to PR1 after peptide immunization.…”

CMRF-56+blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses

“…[1][2][3][4] Nonetheless, recent studies suggest that DC vaccination may have a place in treating both hematological and other malignancies; particularly if applied after a reduction in tumor burden following surgical resection, chemotherapy, or hematopoietic-stem-cell transplantation, when tumor immunosuppression is at its lowest. [5][6][7] Recent trials in acute myeloid leukemia (AML) [8][9][10] and multiple myeloma 7 investigating monocyte derived dendritic cell (Mo-DC) vaccination, after induction chemotherapy and transplantation, have demonstrated objective clinical and immunological responses. To build on this, major improvements in the DC product are needed, first, to address limitations in DC performance and secondly, to make DC vaccination practical.…”

“…If applied after successful conventional induction or consolidation regimes, therapeutic DC vaccination has the much needed potential to induce immune antitumor memory and sustain long-term remission. 7,9,11 DC is divided into several subsets, each with different functional capabilities. Human blood DC (BDC), which are HLA-DR C but lack specific lineage markers, account for approximately 1% of peripheral blood mononuclear cells (PBMC).…”