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

• ClinicalTrials.gov Identifier: NCT02528682
• Recruitment Status: Recruiting
• First Posted: August 19, 2015
• Last Update Posted: April 13, 2020
• Sponsor: Radboud University
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Dutch Cancer Society
• Information provided by (Responsible Party): Radboud University

Tracking Information

• First Submitted Date: August 18, 2015
• First Posted Date: August 19, 2015
• Last Update Posted Date: April 13, 2020
• Study Start Date: January 2016
• Estimated Primary Completion Date: May 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: MiHA-loaded PD-L-silenced DC Vaccination After Allogeneic SCT
• Official Title: 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: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hematological Malignancies

Intervention

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

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 18, 2015): 10
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2020
• Estimated Primary Completion Date: May 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Contact: Olga Huber, Msc; +31-243614794; datacentrum@hemat.umcn.nl

• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT02528682
• Other Study ID Numbers: PSCT19
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Radboud University
• Study Sponsor: Radboud University

Collaborators

• ZonMw: The Netherlands Organisation for Health Research and Development
• Dutch Cancer Society

Investigators

• Principal Investigator: Nicolaas Schaap, MD/PhD; Radboud University

• PRS Account: Radboud University
• Verification Date: November 2019