der Bühne mit den AML Zwischenergebnissen aus den akademischen Studien wie sie auch im Dezember auf der ASH gezeigt wurden:
3rd Immunotherapy of Cancer Conference (ITOC3)
München Monday 21
Poster Session: Anti-Cancer Vaccines
Poster Nr. 65
Next-generation dendritic cell vaccination in postremission therapy of AML: Results of a clinical phase I/II trial
K. Deiser, F. Lichtenegger, F. Schnorfeil, T. Köhnke, T. Altmann, V. Bücklein, A. Moosmann, M. Brüggemann, M.H.M. Heemskerk, B. Wagner, W. Hiddemann, I. Bigalke, G. Kvalheim, M. Subklewe
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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. We have developed a GMP-compliant 3-day protocol including a TLR7/8 agonist to differentiate monocytes of intensively pretreated AML patients into next-generation DCs.
A phase I/II proof-of-concept study has been initiated using next-generation DCs as postremission therapy of AML patients with a non-favorable risk profile in CR after intensive induction therapy (NCT01734304). DCs are loaded with in vitro transcribed RNA encoding the LAAs WT1 and PRAME as well as CMVpp65 as adjuvant and surrogate antigen. Patients are vaccinated intradermally with 5x10e6 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.
Based on the safety and toxicity profile of the phase I trial (n=6), phase II has been initiated. In total, 12 patients have been enrolled into the study. 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. 6 patients have completed the vaccination schedule, while three patients are currently receiving vaccinations. We observed delayed-type hypersensitivity (DTH) responses at the vaccination site in 8/8 patients, accompanied by slight erythema and indurations at the injection site, but no grade III/IV toxicities. TCR repertoire analysis by next-generation sequencing revealed an enrichment of particular clonotypes at DTH sites. Limited by HLA restriction, we have so far analyzed 4 patients by multimer staining. All of them mounted DC vaccination-specific T cell responses: We detected an increase of WT1-specific T cells in one patient and strong expansion/induction of CMVpp65-specific T cells in one CMV-seropositive and two CMV-seronegative patients. In an individual treatment attempt, an enrolled patient with impending relapse was treated with a combination of DC vaccination and 5-azacytidine, resulting in MRD conversion. Long-term disease control and immunological responses are studied in the ongoing phase II trial.
We conclude that vaccination with next-generation LAA-expressing DCs in AML is feasible, safe and induces anti-leukemia-specific immune responses in vivo.
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