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 proof-of-concept study (n=6) was completed using next-generation DCs as postremission therapy of AML patients with a non-favorable genetic risk profile in CR after intensive induction therapy (NCT01734304), and we have already started enrollment into a phase II trial building on these results. DCs are loaded with ivt-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 trial is feasibility and safety of the vaccination. Secondary endpoints are immunological responses and disease control.
In total, 10 patients have been enrolled into the phase I/II trial. With two screening failures, DCs of sufficient number and quality were generated from leukapheresis in 7/8 cases. DC analysis demonstrated a positive costimulatory profile, secretion of IL-12p70, migration towards a chemokine gradient, antigen processing and presentation and activation of specific T cells in vitro. 5 patients have completed the vaccination schedule; the 6th patient has received 4/10 vaccinations. We observed delayed-type hypersensitivity (DTH) responses at the vaccination site in 5/5 patients, accompanied by slight erythema and indurations at the injection site, but no grade III/IV toxicities. Multimer analysis revealed the induction of antigen-specific T cell responses in 3/3 patients tested. We detected an increase of WT1-specific T cells in one patient and strong inductions of CMVpp65-specific T cells in two CMV-seronegative patients. TCR repertoire analysis by next-generation sequencing revealed an enrichment of particular clonotypes at DTH sites. In an individual treatment attempt, we treated one patient with impending relapse with a combination of DC vaccination and 5-azacytidine, resulting in MRD conversion.
From the results of our phase I trial, we conclude that vaccination with next-generation DCs in AML is feasible and safe and induces leukemia-specific immune responses in vivo. The protocol is continued to be studied in an ongoing phase II trial.
Citation Format: Felix S. Lichtenegger, Frauke M. Schnorfeil, Thomas Köhnke, Torben Altmann, Veit Bücklein, Andreas Moosmann, Monika Brüggemann, Beate Wagner, Wolfgang Hiddemann, Iris Bigalke, Gunnar Kvalheim, Marion Subklewe. Next-generation dendritic cell vaccination in postremission therapy of AML: Results of a clinical phase I trial. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B146.
- ©2016 American Association for Cancer Research.