WT-1 and PRAME mRNA transfected TLR 7/8 polarized fast DCs can raise specific immune responses in AML patients that correlate with clinical outcome
Bigalke I.1, Fløisand Y.2, Solum G.1, Hønnåshagen K.1, Skoge L.1, Sæbøe-Larssen S.1, Schendel D.3, Kvalheim G.1
1Oslo University Hospital, The Norwegian Radium Hospital, Department of Cellular Therapy, Oslo, Norway, 2Oslo University Hospital, Oslo, Norway,
3Medigene Immunotherapies GmbH, Martinsried, Germany

Elderly patients with acute myeloid leukemia (AML) often do not tolerate high dose chemotherapy and are currently lacking curative treatment options. Immunotherapy with DC vaccines following induc- tion chemotherapy has been shown by others to have clinical effects in some AML patients. Five AML pa- tients not eligible for bone marrow (BM) transplan- tation and with reduced conditioning/consolidation therapy were treated under hospital exemption with DC vaccines targeting WT-1 and PRAME.
Following informed consent and hematopoietic re- covery after induction chemotherapy monocytes were collected by apheresis and elutriation and matured with a previous described cocktail contain- ing the TLR7/8 ligand R848 resulting in DCs with a polarized release of IL-12p70 and low IL-10 (Sub- klewe et al. 2014).
2.5 or 5E+6 DCs per antigen were injected intrader- mal once weekly for 4 weeks (wks), in wk 6 and there- after in monthly intervals. Blood and bone marrow (BM) samples were collected at regular intervals and minimal residual disease (MRD) was measured in BM by quantitative PCR of WT-1 expression and mor- phology.
Specific T cell responses were assessed by analysis of intracellular interferon gamma expression after stimulation with peptides of WT-1 and PRAME and hTERT and survivin as vaccine unrelated antigens. Patient (Pt) 1 mounted a strong response against PRAME 5 weeks after start of vaccination combined with an unexpected increase in hTERT response,
suggesting that an epitope spreading had taken place. WT-1 signal in BM shows fluctuation in levels between each samples but WT-1 is negative in pe- ripheral blood. The Pt is still in morphological remis- sion 21 months after start of vaccination.
Pt 2 showed initially a WT-1 response. Due to a Bell’s Palsy the patient was given high doses of cortisone. Immediately thereafter immune response was lost and WT-1 increased in BM accompanied by a clinical relapse. In spite of that this patient initially was not eligible for transplantation he was now offered BM transplantation and is currently in remission.
Pt 3 has a fluctuating elevated WT-1 signal in BM but is still in morphological remission under vaccine treatment for 15 months. Immune responses are also fluctuating below the detection limit of our assay. Pt. 4 showed no specific immune responses and re- lapsed after 6 months of DC vaccination. DC treat- ment was continued in combination with 5-Azacy- tidine. The patient was brought into remission and has been treated with this combination therapy for 10 months.
Pt. 5 is in remission now for 5 months since start of vaccination and assessment of immune responses follows.
Altogether, these results show that fast TLR- polar- ized DCs can induce or enhance specific T cell re- sponses with a patient individual pattern. Clinical responses are related to immune responses and can result in prolonged survival in AML patients not eli- gible for curative treatment.
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