While most acute myeloid leukemia (AML) patients achieve a complete remission (CR) with chemotherapy, relapse due to residual disease is common. Allogeneic stem cell transplantation (AlloHCT) addresses this but causes considerable morbidity. Dendritic cell (DC) vaccination has the potential to generate leukaemia-specific immunity with little toxicity.
Previous DC vaccines tested in AML have utilised monocyte-derived DC (Mo-DC), and a growing body of data suggests the functional superiority of blood DC (BDC). We compared the ability of CD1c+ mDC and Mo-DC to present antigen in the context of HLA-A2. CD1c+ mDC presented surface-loading nonamer peptide at higher density than Mo-DC (p=0.0004) and had an increased capacity to cross-present long peptide (p=0.0032). BDC number was then assessed in the peripheral blood of AML patients before and after therapy and compared to age-matched controls. CD1c+ and CD141+ mDC were reduced in active AML (p<0.001) but recovered at CR, whilst pDC showed persistent reductions. The T cell landscape was then assessed at CR and shown to be similar in most patients to controls. However, exposure to fludarabine induced marked T cell abnormalities including reduced number, altered subset distribution, failure to expand, and increased activation-induced cell death upon TCR ligation. CyTOF analysis illustrated altered expression of immune checkpoint molecules on T cells at CR.
BDC were then purified from AML patients in CR and used to expand functional T cell responses to model viral and tumour antigens. After confirming elevated PD-1 and Tim-3 expression on T cells in AML CR patients, we show that BDC induced greater anti-tumour responses in combination with PD-1 and/or Tim3 blockade. This confirms the feasibility of a BDC vaccine for use in AML to prevent relapse from residual disease.