PSCT19: MiHA-loaded PD-L-silenced DC Vaccination After Allogeneic SCT
Study Details
Study Description
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 |
|---|---|---|
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Phase 1/Phase 2 |
Study Design
Arms and Interventions
| 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).
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Outcome Measures
Primary Outcome Measures
- Evaluation of toxicity [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 [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 [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
- Changes in chimerism [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 [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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients with AML, myelodysplasia (MDS), ALL, CML (accelerated or blast phase), CLL, MM, malignant NHL or HL, who underwent HLA-matched allo-SCT
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Patients positive for HLA-A2 and/or HLA-B7
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Patients positive for HA-1, LRH-1 and/or ARHGDIB transplanted with corresponding MiHA-negative donor
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Patients ≥18 years of age
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WHO performance 0-2
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Witnessed written informed consent
Exclusion Criteria:
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Life expectancy < 3 months
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Severe neurological or psychiatric disease
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Progressive disease needing cytoreductive therapy
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HIV positivity
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Patients with acute GVHD grade 3 or 4
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Patients with severe chronic GVHD
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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
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Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease)
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Severe pulmonary dysfunction
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Severe renal dysfunction (serum creatinine > 3 times normal level)
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Severe hepatic dysfunction (serum bilirubin or transaminases > 3 times normal level)
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Patients with known allergy to shell fish
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | 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
- Principal Investigator: Nicolaas Schaap, MD/PhD, Radboud University Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PSCT19