Abstract B002: TLR7/8-matured dendritic cells for therapeutic vaccination in AML: Results of a clinical Phase I/II trial

Postremission therapy for acute myeloid leukemia (AML) is critical for elimination of minimal residual disease (MRD). In patients not eligible for allogeneic stem cell transplantation, alternative treatment options are needed. Therapeutic vaccination with autologous dendritic cells (DCs) loaded with leukemia-associated antigens (LAAs) is a promising treatment strategy to induce anti-leukemic immune responses and to eradicate chemorefractory cells. Using a TLR7/8 agonist, we have developed a GMP-compliant 3-day protocol to differentiate monocytes of intensively pretreated AML patients into highly functional, therapeutic DCs. A phase I/II proof-of-concept study has been initiated using TLR7/8-matured DCs as postremission therapy of AML patients with a non-favorable risk profile in CR or CRi after intensive induction therapy (NCT01734304). DCs have been loaded with in vitro transcribed RNA encoding the LAAs WT1 and PRAME as well as CMVpp65 as adjuvant and surrogate antigen. Patients have been vaccinated intradermally with 5×106 DCs of each antigen species up to 10 times within 26 weeks. The primary endpoint of the phase I/II trial is feasibility and safety of the vaccination. Secondary endpoints are immunological responses and disease control. In total, 13 patients have been enrolled into the study. The first 6 patients were analysed in phase I for safety and toxicity of the DC vaccine. No higher grade toxicities were observed during their treatment and hence phase II has been initiated. DCs of sufficient number and quality were generated from leukapheresis in 10/11 cases. DCs exhibited an immune-stimulatory profile based on high surface expression of positive costimulatory molecules, the capacity to secrete IL-12p70, the migration towards a chemokine gradient and processing and presentation of antigen. In 9/9 vaccinated patients, we observed delayed-type hypersensitivity (DTH) responses at the vaccination site, accompanied by slight erythema and indurations at the injection site, but no grade III/IV toxicities. TCR repertoire analysis by NGS revealed an enrichment of particular clonotypes at DTH sites. In addition, we detected vaccine-specific T-cell responses by multimer staining and by Interferon-gamma-ELISPOT analysis: 7/7 patients showed responses to CMVpp65 and 2/7 exhibited responses to PRAME and WT1, respectively. In an individual treatment attempt, an enrolled patient with impending relapse was treated with a combination of DC vaccination and 5-azacy