Hematological Malignancies
Conditions
Keywords
dendritic cells, PD-L1/L2 silencing, vaccination, stem cell transplantation, minor histocompatibility antigens
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.
Interventions
BIOLOGICALMiHA-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).
Sponsors
ZonMw: The Netherlands Organisation for Health Research and Development
Dutch Cancer Society
Radboud University Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Netherlands
Outcome results
None listed