Leukaemic dendritic cell vaccination for patients with acute myeloid leukaemia

Recently, Roddie et al (2006) reported their experiences with a phase I/II study of vaccination with dendritic cell-like leukaemia cells (DLLC) as immunotherapy for acute myeloid leukaemia (AML). They established that the major drawback of this immunotherapeutical approach is that generation of DLLC is feasible only in a subgroup of AML patients and would therefore not be broadly applicable. However, in a large cohort of 154 patients we were able to induce dendritic cell (DC) differentiation in 66% of AML samples either by culture of AML blasts in presence of a cytokine mix [granulocyte– macrophage colony-stimulating factor, tumour necrosis factor-a (TNF-a), stem cell factor, Flt-3, interleukin (IL)-3, IL-4] or by culture with the calcium ionophore A23187 in combination with IL-4 (Houtenbos et al, 2005). Median AML-DC yield, as defined by upregulation of immunophenotypical DC markers, such as CD40, CD54, CD80, CD86 and CD83, was 12% of the total cell amount (range 0–70%). As AML is a heterogeneous disorder we aimed to identify those factors that could reliably predict DC differentiation inducibility and could therefore be used to select patients eligible for AML-DC vaccination programmes. DC differentiation inducibility of AML blasts appeared to be independent of the French– American–British classification. However, high expression of the surface markers CD14 and TNF-a-RI (CD120a) proved to be highly predictive for the successful DC differentiation of AML blasts cultured in the presence of cytokines (Mohty et al, 2002; Houtenbos et al, 2003, 2004). An alternative culture method, based on the use of calcium ionophores, can be used to induce DC differentiation in CD14 and TNF-a-RI AML samples (Houtenbos et al, 2004). Interestingly, apart from the expression of defined surface markers, the presence of a Flt-3 internal tandem duplication (ITD) was strongly associated with a decreased DC differentiation inducibility of AML blasts by both culture methods, indicating that constitutive activation of the tyrosine kinase receptor may inhibit differentiation (Houtenbos et al, 2005). By combining the aforementioned parameters we developed a model that proved to reliably predict differentiation of AML blasts towards AML-DC in a prospective analysis (Houtenbos et al, 2006a). It would be interesting to analyse the expression of CD14 and TNF-a-RI as well as Flt-3 ITD status in the patient cohort included in the study described by Roddie et al (2006). Patient selection, based on these parameters and use of the calcium ionophore-based culture method, in case of CD14 and TNF-a-RI AML samples are likely to increase the number of patients that will ultimately enter a vaccination programme. Patients with AML blasts that display adverse predictive factors for AML-DC differentiation could benefit from the method suggested by Roddie et al (2006) to load monocyte-derived DC with autologous leukaemic antigens, which is also currently being explored at our laboratories. As also observed in this study, clinically relevant antitumour responses following DC vaccination in a wide variety of malignancies were reported to be minimal. We agree with Roddie et al (2006) that improving the potency of AML-DC vaccines by using agents that enhance AML-DC and T-cell functions are likely to be necessary to make DC vaccines worthwhile in leukaemia. However, apart from improving vaccine potency by manipulation of DC maturation or systemic administration of immunomodulatory cytokines, AML-DC should also better overcome the intrinsic tolerant state of the patient. Strategies to sensitise residual leukaemic cells and their microenvironment, e.g. by blocking regulatory T cells or neutralising antibodies to inhibitory interleukins secreted by the microenvironment of AML blasts might be required to shift the patients’ immune state from tolerance towards immunising and convert subclinical responses towards AML-DC vaccination to clinical relevant anti-leukaemic responses (Houtenbos et al, 2006b).