A phase I/II post-cord blood HCT dendritic cell vaccination trial directed against WT1 for pediatric acute myeloid leukemia: the U-DANCE-anti-AML trial

Development of novel (immune) therapies aimed at reducing relapse rates
(currently 50%) is of utmost importance to improve survival chances in
pediatric acute myeloid leukemia (AML) patients receiving stem cell
transplantation, in this case cord blood transplantation (CBT).
We hypothesize that tumor antigen-loaded cord blood-derived dendritic cell
(CBDC) vaccination combined with the intrinsic anti-leukemic and proliferative
capacity of the grafted CB T cells will result in fast proliferation and
differentiation of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs).
Wilms Tumor 1 (WT1) is an oncoprotein overexpressed in the majority of AMLs. As
such, the CBDC vaccine will be loaded with tumor antigen using WT1
mRNA-electroporation and WT1 15-mer-peptide pool-pulsing. This loading strategy
ensures MHC class I and II presentation without any HLA restriction and enables
induction of both WT1-specific CD8 and CD4 responses, which is required for the
induction of immunological memory and optimal anti-tumor immunity.

Although DC vaccinations have been used in allo-HCT settings, no previous
studies have been performed using a CBDC vaccine after CBT. This study will
therefore be subdivided into 2 parts:

- Part A: to determine a safe dose of the vaccination, and
- Part B: to study its activity measured as the one-year relapse-free survival
rate, based on an expansion cohort.

Part A primary objective:
- To assess the safe dose for CBDC vaccination after CBT defined using the
occurrence of dose limiting toxicities (DLTs), including acute graft versus
host disease (aGVHD). The DLT evaluation period lasts from the first
vaccination, until 84 days after the third CBDC vaccination.

Part A secondary objectives:
- To assess the safety and tolerability of the vaccination strategy
- To assess the induction/increase of WT1-specific immunity in vaccinated
individuals during one year of follow-up from the first vaccination
- To assess overall survival at one year after the first vaccination
- To assess WT1+ AML relapse-free survival at one year after the first
vaccination
- To assess the chronic GvHD (cGvHD) occurrence during one year of follow-up
from the first vaccination


Part B primary objective:
- To demonstrate an increase in the WT1+ AML relapse-free survival rate using a
WT1-loaded CBDC vaccine, at one year after the first vaccination (using a
historic cohort not receiving a CBDC vaccination as reference data for the
Simon-2-stage design).

Part B: secondary objectives:
- To assess the safety and tolerability of the vaccination strategy
- To assess the induction/increase of WT1-specific immunity in vaccinated
individuals during one year of follow-up from the first vaccination
- To assess overall survival at one year after the first vaccination
- To assess the cGvHD occurrence during one year of follow-up from the first
vaccination (as compared to our historic cohort not receiving a CBDC
vaccination).


Part B: exploratory objectives:
- To assess general (non-WT1 specific) immune activation in each vaccinated
individual during one year of follow-up from the first vaccination compared to
the immune parameters before vaccination.
- To assess the expression of inhibitory (immune checkpoint) molecules on AML
in the case of relapse during one year of follow-up from the first vaccination

This is a single-arm open-label phase I/II intervention study in pediatric AML
patients using an advanced therapeutic medicinal product `(ATMP): cord
blood-derived dendritic cell (CBDC) vaccine. Data from our historic cohort of
pediatric patients with a WT1+ AML and receiving CBT will be used as control
group for the primary objective in part B.

CBDC-vaccination (day 0, day 14 and day 28):
Patients will receive three *Full length WT1 encoding* mRNA-electroporated and
WT1 15-mer-peptide pool loaded CBDC-vaccinations starting at 8 weeks post-CBT
every 2 weeks (hence week 8, 10 and 12). The CBDC vaccine will be split into
two equal doses that will be administered intradermally and intravenously.

Potential burden:
* The intradermal injections may be experienced as painful (for this we will
apply local anesthetics using *lidocaine-tetracaine* (Rapidan-plasters).
* Repeated intradermal injection may lead to local skin reaction characterized
by erythema.
* Combined intradermal and intravenous vaccinations have been reported to cause
signs of mild fatigue, fever, chills, anorexia and muscular pain starting as
soon as time of vaccination but never lasting beyond two days after vaccination
and always within grade 1-2
Since these vaccination related symptoms are generally mild, do not require
medical interventions and are short lived their occurrence will not be
considered as DLTs.

Additional risk of the CBDC vaccination:
* Induction of moderate / severe aGvHD (grade II * IV)
* Induction of cGvHD

Potential Benefits:
* Higher probability on continuous complete remission of AML
* Prolonged survival (Long-term stabilization of disease levels)

Taken together it is our opinion that the potential benefits (reduced relapse
and enhanced survival) outweigh the potential risks (GvHD).

Group relatedness:
This study is developed to reduce the frequency of relapses in pediatric AML
and hence cannot be studied in other populations.