MiHA-loaded PD-L-silenced DC Vaccination After Allogeneic SCT (PSCT19)

Tracking Information
First Submitted Date ICMJE	August 18, 2015
First Posted Date ICMJE	August 19, 2015
Last Update Posted Date	September 13, 2018
Study Start Date ICMJE	January 2016
Estimated Primary Completion Date	July 2019 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: August 18, 2015)	Evaluation of toxicity [ Time Frame: From day 0 until day 84 ]Toxicity will be measured using the NCI CTCAE criteria (http://ctep.cancer.gov/reporting/ctc.html). Possible toxicities include constitutional symptoms such as fever, chills, myalgias, malaise and allergic reactions.; Development of GVHD [ Time Frame: From day 0 until day 84 ]DC vaccination may result in GVHD, which will be scored and treated if indicated according to standard guidelines.; The generation and magnitude of an immunological response [ Time Frame: From day 0 until day 84 ]When after DC vaccination >1.0% of all CD8+ lymphocytes at any time point are specific CD8+ T cells to the used MiHA vaccine target, a complete response will be considered to be present. When the percentage is between 0.02% and 1%, but has been doubled during two weeks, a partial immune response will be considered to be present.
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT02528682 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: August 18, 2015)	Changes in chimerism [ Time Frame: day 0, day 14, day 28, day 64, day 84 ]When chimerism changes towards donor or disease load decreases according to objective standard clinical criteria after vaccination, this will be considered as a clinical response. Chimerism in PBMC will be measured by SNP Q-PCR analysis according to standard practice in the molecular diagnostic unit of Department of Laboratory Medicine. When chimerism changes towards complete donor, this will be considered as a clinical response.; Disappearance of residual disease [ Time Frame: day 0, day 14, day 28, day 64, day 84 ]In the case of presence of detectable residual or persistent disease before DC vaccination, clinical effects will be investigated by monitoring residual disease by quantitative real-time bcr-abl PCR (CML, Ph+ ALL), WT1-specific PCR (AML, MDS), M-protein (MM), immunophenotyping (CLL, AML, ALL, MDS) and radiological examination (NHL) after vaccination. When disease load decreases according to objective standard clinical criteria after vaccination, this will be considered as a clinical response.
Original Secondary Outcome Measures ICMJE	Same as current
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	MiHA-loaded PD-L-silenced DC Vaccination After Allogeneic SCT
Official Title ICMJE	Vaccination With PD-L1/L2-silenced Minor Histocompatibility Antigen-loaded Donor DC Vaccines to Boost Graft-versus-tumor Immunity After Allogeneic Stem Cell Transplantation (a Phase I/II Study)
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. We found that the PD-1/PD-L1 co-inhibitory pathway is involved in dampening MiHA-specific CD8+ T cell expansion and function post-transplantation. Therefore, a promising strategy to induce or boost GVT immune responses is pre-emptive or therapeutic vaccination with ex vivo-generated donor DCs 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 graft-versus-host disease (GVHD) and the potency to induce more efficient GVT-associated T cell immunity. In addition, the potency of this DC vaccine will be further enhanced by interference with the PD-1/PD-L1 co-inhibitory pathway, using siRNA mediated PD-L1/PD-L2 silencing.
Detailed Description	Not Provided
Study Type ICMJE	Interventional
Study Phase	Phase 1; Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Hematological Malignancies
Intervention ICMJE	Biological: MiHA-loaded PD-L-silenced DC Vaccination; Eligible patients will receive one cycle of donor DC vaccination consisting of maximal 3 immunizations, given at 2 week intervals. PD-L1/L2-silenced, MiHA mRNA-electroporated donor DC will be infused intravenously (2.5x105/kg body weight).
Study Arms	Experimental: Single arm; MiHA-loaded PD-L-silenced DC Vaccination; Intervention: Biological: MiHA-loaded PD-L-silenced DC Vaccination
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Recruiting
Estimated Enrollment ICMJE; (submitted: August 18, 2015)	10
Original Estimated Enrollment ICMJE	Same as current
Estimated Study Completion Date	July 2019
Estimated Primary Completion Date	July 2019 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Patients with AML, myelodysplasia (MDS), ALL, CML (accelerated or blast phase), CLL, MM, malignant NHL or HL, who underwent HLA-matched allo-SCT; Patients positive for HLA-A2 and/or HLA-B7; Patients positive for HA-1, LRH-1 and/or ARHGDIB transplanted with corresponding MiHA-negative donor; Patients ≥18 years of age; WHO performance 0-2; Witnessed written informed consent 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 severe chronic GVHD; Patients with active infections (viral, bacterial or fungal) that require 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; 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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact: Olga Huber, Msc +31-243614794 datacentrum@hemat.umcn.nl
Listed Location Countries ICMJE	Netherlands
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT02528682
Other Study ID Numbers ICMJE	PSCT19
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Radboud University
Study Sponsor ICMJE	Radboud University
Collaborators ICMJE	ZonMw: The Netherlands Organisation for Health Research and Development; Dutch Cancer Society
Investigators ICMJE	Principal Investigator: Nicolaas Schaap, MD/PhD Radboud University
PRS Account	Radboud University
Verification Date	September 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP