A phase I/II *minor histocompatibility antigen UTA2-1 loaded, PD-L silenced Dendritic cell vaccination trial after allogeneic Stem Cell Transplantation to improve the safety and efficacy of Donor Lymphocyte Infusions.

Allogeneic stem cell transplantation (allo-SCT) is the only curative option for
a number of hematological malignancies including acute and chronic leukemia,
lymphoma and myeloma, due to a donor T cell-mediated Graft versus Tumor effect
(GvT). Unfortunately sustained complete remissions are only achieved in 30-60%
of patients depending on disease category and disease characteristics. Donor
lymphocyte infusions (DLI) are routinely applied in patients with relapsed or
residual disease after allo-SCT. However, only a minority of patients responds
to DLI. Furthermore DLI can cause severe and sometimes fatal side effects
mainly due to Graft versus Host Disease (GvHD). Therefore strategies are
urgently needed to improve the efficacy and safety of DLI.
An attractive strategy to improve the safety and efficacy of DLI is targeting
donor T cells towards hematopoietic-system-specific minor histocompatibility
antigens (minor H ags). We have recently discovered the UTA2-1, a novel HLA-A2
restricted hematopoietic minor H ag antigen with a ~60% population frequency
and high expression in multiple myeloma (MM) and B cell malignancies. We now
propose a vaccination strategy, in which patients with MM and B cell
malignancies such as chronic lymphocytic leukemia (CLL) and Non-Hodgkin
Lymphomas, who are not responding to a first DLI will be treated with a second
DLI combined with a therapeutic vaccine consisting of donor DCs loaded with the
peptides of UTA2-1 minor H ag. Since recent evidence indicates that
co-inhibitory PD-L1/2 molecules present on DCs can negatively influence the
generation of minor H ag T cell responses, we will also knock down these
molecules on DCs by an innovative siRNA technology.
This approach is built on the following well established concepts:
i) Dendritic cells (DCs) are the best known professional antigen presenting
cells, considered crucial for the development of an adequate immune response,
ii) minor H ags are the main targets of donor T cells inducing GvT,
iii) targeting donor T cells against hematopoietic minor H ags can induce a
specific anti-tumor response without increasing the risk for GVHD.
iv) we have recently shown that DLI combined with minor H ag-peptide pulsed
recipient- or donor-DC vaccination is clinically feasible, safe and induces
peptide specific T cell responses (unpublished results).

Primary objectives:

- To evaluate the toxicity and feasibility of a DLI-combined minor H ag UTA2-1
peptide-loaded, PD-L silenced donor DC vaccination in B cell hematological
malignancies
- To evaluate the effect of a DLI-combined minor H ag UTA2-1 peptide-loaded,
PD-L silenced donor DC vaccination on the immune status of the recipient in
correlation with toxicity and response


Secondary objective:

- To evaluate the efficacy of the DLI-combined minor H ag UTA2-1
peptide-loaded, PD-L silenced donor DC vaccination to induce a GvT for B cell
hematological malignancies.

A single center phase I/II trial with the primary goal to evaluate the safety
and efficacy of a combined DLI and DC vaccination strategy
tor relapsed or residual disease after donor stem cell transplantation and a
previous DLI.
Study endpoints are grade 4 CTC toxicity, late ons et acute GvHD grade 3 and 4.
For clinical efficacy response criteria related to the different hematological
malignancies will be applied.

Suitable patients will be treated with a combined infusion of DLI (same dose as
the first DLI) with ex vivo cultured donor DCs that are a) stripped of PD-L
molecules by means of a siRNA transfection methodology and b) loaded with
peptides of the UTA2-1 antigen. DCs will be administered at a total dose of
45-90x10^6 DCs, in 3 servings with two weeks intervals; only the first
administration will be combined with DLI. Patients will be examined for the
occurrence of side-effects, anti-tumor effect, influence on the immune system
and the development of specific immune responses against the UTA2-1 antigen.
Upon positive results of the research this vaccination strategy can become a
standard treatment for the treatment of appropriate patients with malignant
hematologic diseases, with the ultimate aim to increase the chances of cure.

Burden associated with participation: The usual procedure tor patients nat
raspondingtoa first DLI is a second DLI
containing a higher T cell dose . Patients included in the vaccination trial
will receive the same T cell dose combined with
the DC vaccination. For both categories of patients routine investigations at
the out patient clinic are performed in weekly or two weekly intervals to
monitor the general physical status and tumor load of the patients . This may
include bone marrow investigations, immune phenotyping and cytogenetics and
imaging techniques like CT scans, MRI and/or PET scans . Extra study procedures
include: DC vaccinations, 3 times repeated with an interval of 2 weeks. Blood
sampling for evaluation of the immune effects: 40 mi of blood will be obtained
at week -2 and at weeks 0, 1, 2, 4, 6, 10, 14 and 20 after the first
vaccination.
Risks associated with the investigational product. Potential risk is the
induction of GvHD. Ta minimize this side effect we will infuse the same T cell
dose as given with the first DLI and maintain an interval of at least 10 weeks
between the first and second DLI. In addition to avoid overlapping toxicities
we will keep an interval of 4 weeks between recruiting in the first 3 patients
and starting the DLI + vaccination. This will allow interrupting the
vaccination scheme in the following patients in case unacceptable toxicity is
observed in the preceding patient. In previous phase I/II trials of DLI
combined with peptide loaded host or donor DC's, no toxicity (GvHD) was
recorded. In the current trial we will use only UTA2-1, a strictly
haematopoietic restricted antigen. Therefore we expect no GvHD, but cannot
exclude excessive toxicity. For this reason toxicity is one of the major
endpoints of the study.
Benefit: A second dose escalated DLI is the standard next treatment step for
patients not responding to a first DLI. This
procedure is associated with a substantial risk of severe, sometimes fatal
GvHD. If proven feasible and effective, (sustained) complete remissions may be
achieved in patients with an otherwise fatal outcome of their disease.