|- candidate number||15293|
|- NTR Number||NTR4128|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||19-aug-2013|
|- Secondary IDs||NL41183.000.12 (CCMO), 2012-002879-34 (EudraCT) |
|- Public Title||MiHA-DC vaccinatie na allogene stamceltransplantatie.|
|- Scientific Title||Vaccination with minor histocompatibility antigen-loaded donor DC vaccines to boost graft-versus-tumor immunity after allogeneic stem cell transplantation (a phase I study).|
|- Healt Condition(s) or Problem(s) studied||PSCT16, MiHA-DC|
|- Inclusion criteria||- Patients positive for HLA-A2 and/or HLA-B7.|
- Patients positive for HA-1, LRH-1 and/or ARHGDIB transplanted with the corresponding MiHA-negative donor.
- Patients >18 and <65 years of age.
- WHO performance status 0-2.
|- Exclusion criteria||- Life expectancy < 3 months.|
- Severe neurological or psychiatric disease.
- Progressive disease needing cytoreductive therapy.
- HIV positivity.
- Patients with acute GVHD grade 3 or 4.
- Patients with extensive chronic GVHD.
- Patients with active infections (viral, bacterial or fungal) that requires specific therapy. Acute anti-infectious therapy must have been completed within 14 days prior to study treatment.
- Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease).
- Severe pulmonary dysfunction (CTCAE III-IV).
- Severe renal dysfunction (serum creatinine > 3 times normal level).
- Severe hepatic dysfunction (serum bilirubin or transaminases > 3 times normal level).
- Patients with known allergy to shell fish.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||Single arm|
|- planned startdate ||19-aug-2013|
|- planned closingdate|
|- Target number of participants||0|
|- Interventions||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).|
|- Primary outcome||The primary study parameters are to evaluate the safety, toxicity, development of GVHD and the immunological response by appearance of MiHA-specific CD8+ T cells following vaccination with monocyte-derived donor DC electroporated with mRNA encoding hematopoietic-restricted MiHA in patients who had undergone allo-SCT with stem cells from a HLA-matched, MiHA-mismatched donor.|
|- Secondary outcome||The secondary study parameters are to evaluate the clinical effect of MiHA-DC vaccination in case of detectable minimal residual disease and mixed chimerism.|
|- Timepoints||- 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.
|- Trial web site||N/A|
|- CONTACT FOR PUBLIC QUERIES||drs O. Huber|
|- CONTACT for SCIENTIFIC QUERIES|| Nicolaas P.M. Schaap|
|- Sponsor/Initiator ||Radboud University Medical Center Nijmegen|
(Source(s) of Monetary or Material Support)
|ZON-MW, The Netherlands Organization for Health Research and Development, KWF Kankerbestrijding|
|- Brief summary||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.
|- Main changes (audit trail)|
|- RECORD||19-aug-2013 - 2-sep-2013|