A phase I/II trial to boost the graft-versus-tumor effect of Allogeneic Stem Cell Transplantation by vaccination with PD-L silenced, minor histocompatibility antigen UTA2-1 peptide-loaded Dendritic Cells

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 allo SCT 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), B cell malignancies and in acute
myeloid leukemia(AML). We now propose a vaccination strategy, in which above
mentioned patients will be preemtively treated with a therapeutic vaccine
consisting of donor DCs loaded with the peptides of UTA2-1 minor Hag. 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 mHag pulsed DC vaccionations of patients even combined with a DLI is
clinically feasible, safe and induces peptide specific T cell responses.

Primary objectives:

- To evaluate the toxicity and feasibility of a preemptive minor H ag UTA2-1
peptide-loaded, PD-L silenced donor DC vaccination.
- To evaluate the effect of a 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 in patients
with meaurable residual tumor load.

A single center phase I/II trial with the primary goal to evaluate the safety
and efficacy of a preemptve DC vaccination strategy after donor stem cell
transplantation.
Study endpoints are CTC toxicity grade 3 and 4 , b. Acute and chronic GvHD, c.
Clinical response and duration of response , d. Immune effects including minor
H ag UTA2-1-specific CD8+ T cell responses.

For clinical efficacy response criteria related to the different hematological
malignancies will be applied.

Suitable patients will be vaccinated with ex vivo cultured donor DCs that are
a) silenced for 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 intervalsPatients
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 procedures include a total of 3 DC vaccinations, 3 times repeated with an
interval of 2 weeks between each vaccination: blood sampling for evaluation of
the immune effects: 40 ml of blood will be obtained at week -2 and at weeks 0,
1, 2, 4, 6, 10, 14 and 20 after the first vaccination. In addition, routine
investigations at the out patient clinic weekly or two weekly are performed to
monitor the general physical status and tumor load of the patients. This may
include bone marrow investigations, immune phenotyping and imaging techniques
like CT scans, MRI and/or PET scans.

Risks associated with the investigational product.

The major potential risk in therapeutic interventions after allo SCT is the
induction of GvHD.
In our two previous phase I/II trials we combined unloaded or peptide loaded
host or donor DC vaccinations with DLI. No GvHD or other toxicity was recorded
in these trials. Since in the current trial we will use only hematopoietic
restricted minor H ag UTA2-1 loaded on donor DCs in a preemptive way, thus
without combining the vaccination with DLI, we expect no GvHD associated with
DC vaccinations. However, in this trial the donor DCs will be silenced for
co-inhibitory molecules PD-L1and PD-L2. Therefore (GvHD related) toxicity is
still one of the major endpoints of the study since such a PD-L silenced,
peptide loaded donor DC vaccination has never been applied before.
Therefore, to avoid overlapping toxicities we will keep an interval of 6 weeks
between recruiting for the first 3 patients and starting the vaccination. This
will allow interrupting the vaccination scheme in the following patients if an
unacceptable toxicity occurs in the preceding patient

Benefit: DLI is the standard next treatment step for patients with residual
disease after allo-SCT. This procedure is associated with a substantial risk of
severe and sometimes fatal GvHD. If proven feasible and effective, (sustained)
complete remissions may be achieved through DC vaccination in patients with an
otherwise fatal outcome of their disease.