Clinical Trials /

MiHA-loaded PD-L-silenced DC Vaccination After Allogeneic SCT

NCT02528682

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Chronic Lymphocytic Leukemia
  • Chronic Myeloid Leukemia
  • Hodgkin Lymphoma
  • Multiple Myeloma
  • Myelodysplastic Syndromes
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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)

Clinical Trial IDs

  • ORG STUDY ID: PSCT19
  • NCT ID: NCT02528682

Conditions

  • Hematological Malignancies

Interventions

DrugSynonymsArms
MiHA-loaded PD-L-silenced DC VaccinationSingle arm

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Single armExperimentalMiHA-loaded PD-L-silenced DC Vaccination
  • MiHA-loaded PD-L-silenced DC Vaccination

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluation of toxicity
Time Frame:From day 0 until day 84
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Changes in chimerism
Time Frame:day 0, day 14, day 28, day 64, day 84
Safety Issue:
Description: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.
Measure:Disappearance of residual disease
Time Frame:day 0, day 14, day 28, day 64, day 84
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Radboud University

Trial Keywords

  • dendritic cells
  • PD-L1/L2 silencing
  • vaccination
  • stem cell transplantation
  • minor histocompatibility antigens

Last Updated

November 21, 2019