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.
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
Drug | Synonyms | Arms |
---|
MiHA-loaded PD-L-silenced DC Vaccination | | Single 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
Name | Type | Description | Interventions |
---|
Single arm | Experimental | MiHA-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: | Completed |
Lead Sponsor: | Radboud University |
Trial Keywords
- dendritic cells
- PD-L1/L2 silencing
- vaccination
- stem cell transplantation
- minor histocompatibility antigens
Last Updated
April 1, 2021