MiHA-DC vaccinatie na allogene stamceltransplantatie.

Allogeneic stem cell transplantation (allo-SCT) is a potent treatment and sometimes the only curative treatment for aggressive hematological malignancies. The therapeutic efficacy is attributed to the graft-versus-tumor (GVT) response, during which donor-derived CD8+ T cells become activated by recipient minor histocompatibility antigens (MiHA) presented on dendritic cells (DC). Consequently, these alloreactive donor T cells clonally expand, acquire effector functions and kill MiHA-positive malignant cells. However, in a substantial number of patients persistence and recurrence of malignant disease is observed, indicating that insufficient GVT immunity is induced. This is reflected by our observation that not all patients develop a productive CD8+ T cell response towards MiHA mismatched between the recipient and donor. A promising strategy to induce or boost GVT immune responses is pre-emptive or therapeutic vaccination with ex vivo-generated donor DC loaded with MiHA that are exclusively expressed by recipient hematopoietic cells and their malignant counterparts. In contrast to pre-emptive donor lymphocyte infusion (DLI) with polyclonal donor T cells, this MiHA-DC vaccination approach has less risk of inducing GVHD and the potency to induce more efficient GVT-associated T cell immunity.



This study will be performed in the Netherlands.

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- Safety, toxicity and development of GVHD will be monitored with standard physical examination at weekly or two-weekly visits to the outpatient clinic. General toxicity of the DC vaccinations will be measured using the NCI CTCAE criteria (http://ctep.cancer.gov/reporting/ctc/html).

- Immunological responses will be monitored in peripheral blood samples obtained at day 0 (prior to first DC vaccination) and day 7, 14, 21, 28, 42, 63 and 84 after DC vaccination. Peripheral blood will be used for monitoring of T cell responses: changes in T/B/NK subsets by flow cytometry immunophenotyping, detection of MiHA-specific CD8+ T cells (% MiHA-tetramer-positive cells with flow cytometry), specific T cell proliferative and cytokine responses against KLH (in vitro restimulation assay). In addition, serum samples will be collected at each time point and stored at -20°C until use for monitoring of humoral immune responses: presence of antibodies against KLH will be examined by ELISA.

- Chimerism in peripheral blood (day 0, 14, 28, 63 and 84) will be measured by SNP Q-PCR analysis according to standard practice in the molecular diagnostic unit of the Department of Laboratory Medicine.

- In case of presence of detectable residual or persistent disease before DC vaccination, clinical effects will be investigated by monitoring residual disease in peripheral blood (day 0, 14, 28, 63 and 84) or bone-marrow aspirates (day 0, 42 and 84) using quantitative real-time bcr-abl PCR (CML, Ph+ ALL), WT1-specific PCR (AML, MDS), M-protein (MM), immunophenotyping (CLL, AML, ALL, MDS) or radiological examination (NHL) after vaccination.

Eligible patients will receive once cycle of DC vaccination consisting of maximal 3 immunizations, given at 2 week intervals. MiHA mRNA-electroporated donor DC will be infused intravenously (2.5x105/kg body weight).