The primary objectives of our study are to evaluate safety, toxicity and capability of inducing T cell responses of vaccination with, monocyte-derived donor DC transfected with PD-L1/L2 siRNA and electroporated with mRNA encoding hematopoietic-…
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Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study parameters are to evaluate the safety, toxicity, development
of GVHD and the immunological response by appearance of MiHA-specific CD8+ T
cells following vaccination with monocyte-derived donor DC transfected with
PD-L1/L2 siRNA and electroporated with mRNA encoding hematopoietic-restricted
MiHA in patients who had undergone allo-SCT with stem cells from HLA-matched,
MiHA-mismatched donor.
Secondary outcome
The secondary study parameters are to evaluate the clinical effect of MiHA-DC
vaccination in case of detectable minimal residual disease and mixed chimerism.
Background 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 mismatched MiHA between the recipient and donor. A
promising strategy to induce or boost GVT immune responses is pre-emptive or
therapeutic vaccination with ex vivo-generated PD-L1/L2-silenced donor DC
loaded with MiHA that are exclusively expressed by recipient hematotopoietic
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 GVHD and the potency to induce
more efficient GVT-associated T cell immunity.
Study objective
The primary objectives of our study are to evaluate safety, toxicity and
capability of inducing T cell responses of vaccination with, monocyte-derived
donor DC transfected with PD-L1/L2 siRNA and electroporated with mRNA encoding
hematopoietic-restricted MiHA in patients who had undergone allo-SCT with stem
cells from HLA-matched, MiHA-mismatched donor. The secondary objective is to
evaluate the clinical effect of vaccination in case of detectable minimal
residual disease and mixed chimerism
Study design
This is a phase I/II study in a series of 10 allo-SCT recipients. Eligible
patient include MiHA-mismatched patients who do not develop aGVHD * grade 2 or
extensive cGVHD after stopping cyclosporine A, and have no or limited
MiHA-specific T cell response (defined by *1.0% of total CD8+ T cells). These
eligible patients will receive pre-emptive MiHA-DC vaccination.
Intervention
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 (2.5x10^5/kg body
weight).
Study burden and risks
Participating patients will visit the outpatient clinic weekly or two-weekly
for standard physical examination and blood sampling from the first DC
vaccination until 12 weeks after the first DC vaccination. For follow-up,
peripheral blood will be collected from patients pre-study, at day 0, 7, 14,
21, 28, 42, 63 and 84 during and after DC vaccinations. The total amount of
extra blood that will be taken for study purposes will be maximally 315 ml in a
three month period. Three extra bone marrow aspirations will be performed
(Pre-study, day 42 and 84 after first DC vaccination).
Theoretically, the risk of MiHA-DC vaccination is the development of a strong T
cell response inducing GVHD or an anaphylactic reaction. However, as the MiHA
HA-1, LRH-1 or ARHGDIB are expressed only by hematopoietic cells we do not
expect severe acute GVHD. Furthermore, because CD8+ T cell responses against
these hematopoietic-restricted MiHA occur in allo-SCT patients by nature, we do
not expect a systemic anaphylactic reaction. Indeed in a previous
post-transplantation vaccination study with recipient-derived DCs expressing
endogenous MiHA, the toxicity was limited to low-grade fever and chills, but
none of the patients developed GVHD (Levenga et al. BBMT 2010). Finally, when
MiHA-DC vaccination indeed yields a productive immune response, with increasing
donor chimerism and/or reducing residual disease, there is no need for a next
DLI thereby decreasing the risk of acute GVHD. In addition, DC-induced
MiHA-specific CD8+ T cell responses could be associated with a lower relapse
rate.
Geert Grooteplein Zuid 8
Nijmegen 6525GA
NL
Geert Grooteplein Zuid 8
Nijmegen 6525GA
NL
Listed location countries
Age
Inclusion criteria
Patient inclusion criteria
* Patients with AML, myelodysplasia (MDS), ALL, CML (accelerated or blast phase), CLL, MM or malignant NHL, 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
Exclusion criteria
Patient 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
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-003537-26-NL |
| CCMO | NL49913.000.14 |