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

NCT ID: NCT02528682

Last Updated: 2021-04-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-01-31
• Study Completion Date: 2021-03-31

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.

Conditions

Hematological Malignancies

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Single arm

MiHA-loaded PD-L-silenced DC Vaccination

Group Type: EXPERIMENTAL

MiHA-loaded PD-L-silenced DC Vaccination

Intervention Type: BIOLOGICAL

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).

Interventions

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).

Intervention Type: BIOLOGICAL

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

Dutch Cancer Society

OTHER

Sponsor Role: collaborator

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nicolaas Schaap, MD/PhD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

Trialoffice Haematology-Oncology

Nijmegen, Gelderland, Netherlands

Countries

Netherlands

Other Identifiers

PSCT19

Identifier Type: -

Identifier Source: org_study_id