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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02528682
Recruitment Status : Completed
First Posted : August 19, 2015
Last Update Posted : April 1, 2021
Sponsor:
Collaborators:
ZonMw: The Netherlands Organisation for Health Research and Development
Dutch Cancer Society
Information provided by (Responsible Party):
Radboud University Medical Center

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.

Condition or disease Intervention/treatment Phase
Hematological Malignancies Biological: MiHA-loaded PD-L-silenced DC Vaccination Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Study Start Date : January 2016
Actual Primary Completion Date : March 31, 2021
Actual Study Completion Date : March 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vaccines

Arm Intervention/treatment
Experimental: Single arm
MiHA-loaded PD-L-silenced DC Vaccination
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).




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.


Secondary Outcome Measures :
  1. 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.


  2. 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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02528682


Locations
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Netherlands
Trialoffice Haematology-Oncology
Nijmegen, Gelderland, Netherlands, 6500 HB
Sponsors and Collaborators
Radboud University Medical Center
ZonMw: The Netherlands Organisation for Health Research and Development
Dutch Cancer Society
Investigators
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Principal Investigator: Nicolaas Schaap, MD/PhD Radboud University Medical Center
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Responsible Party: Radboud University Medical Center
ClinicalTrials.gov Identifier: NCT02528682    
Other Study ID Numbers: PSCT19
First Posted: August 19, 2015    Key Record Dates
Last Update Posted: April 1, 2021
Last Verified: January 2021
Keywords provided by Radboud University Medical Center:
dendritic cells
PD-L1/L2 silencing
vaccination
stem cell transplantation
minor histocompatibility antigens
Additional relevant MeSH terms:
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Hematologic Neoplasms
Neoplasms
Neoplasms by Site
Hematologic Diseases