PuSH - Publikationsserver des Helmholtz Zentrums München

Deiser, K. ; Lichtenegger, F.S. ; Schnorfeil, F.M. ; Köhnke, T.* ; Altmann, T.* ; Buecklein, V.* ; Moosmann, A. ; Brueggemann, M.* ; Wagner, B.* ; Hiddemann, W.* ; Bigalke, I.* ; Kvalheim, G.* ; Subklewe, M.

Next-generation dendritic cell vaccination in postremission therapy of AML: Results of a clinical phase I trial.

Blood 126:3805 (2015)
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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 genetic 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 5x106 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, 10 patients have been enrolled into the study. DCs of sufficient number and quality were generated from leukapheresis in 8/9 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. 5 patients have completed the vaccination schedule; the 6th and 7th patient have received 7/10 and 4/10 vaccinations, respectively. We observed delayed-type hypersensitivity (DTH) responses at the vaccination site in 6/6 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.
Weitere Metriken?
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Meeting abstract
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Zeitschrift Blood
Quellenangaben Band: 126, Heft: 23, Seiten: , Artikelnummer: 3805 Supplement: ,
Verlag American Society of Hematology
Verlagsort Washington
Begutachtungsstatus Peer reviewed
Institut(e) CCG Hematopoetic Cell Transplants (IMI-KHZ)
CCG Immunooncology (AGV-KIO)
CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)