A phase I/II trial towards the safety and efficacy of preemptive vaccination with PD-L silenced, minor histocompatibility antigen UTA2-1 peptide-loaded Dendritic Cells after Allogeneic Stem Cell Transplantation

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.
Furthermore allo SCT 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 allo SCT. 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
Hags). We have recently discovered the UTA2-1, a novel HLA-A2 restricted
hematopoietic minor Hag antigen with a ~60% population frequency and high
expression in multiple myeloma (MM), B cell malignancies and in acute myeloid
leukemia (AML). We have recently shown that after a failed low dose Donor
lymphocyte infusion (DLI) a second low dose DLI combined with vaccination of
patients with DCs loaded with the peptides of minor Hags, including UTA2-1, is
clinically feasible, safe and induces peptide specific T cell responses, but in
a minority of patients. Furthermore these responses were not sufficiently
robust to induce meaningful clinical responses in these DLI no responder
patients, indicating that the vaccination strategy needs to be improved toward
achieving better immune responses. Recently it became clear that the DC antigen
presentation capacity can be significantly improved by knocking out the two
important inhibitory molecules, PD-L1 and PD-L2. We therefore now propose an
improved strategy, in which UTA2-1 positive patients, who underwent an allo
transplantation from an UTA2-1 negative donor will be vaccinated with UTA2-1
loaded, PD-L1/L2 knocked out donor DCs, in a pre-emptive fashion, just after
stopping the GvHD preventive treatment, where the tumor load is very low or
barely detectable.

- 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

A single center phase I/II trial with the primary goal to evaluate the safety
and efficacy of a preemptive vaccination strategy with UTA2-1 loaded, PDL1/L2
silenced DCs 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, UTA2-1 peptide
loaded donor DCs that are furthermore silenced for PD-L1/L2 molecules via
siRNA transfection DCs will be administered at a total dose of minimal 45 and
maximal 90x10^6 DCs, in 3 servings with two weeks intervals. 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 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 outpatient 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, immunophenotyping 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 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.