A phase I/II post-cord blood HCT dendritic cell vaccination trial directed against WT1 for pediatric and young adult 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
15-mer-peptide pool-pulsing. This loading strategy used 2 antigen processing
pathways ensuring maximum MHC class I and II presentation without any HLA
restriction. This enables induction of both WT1-specific CD8 and CD4 responses,
which is required for the induction of immunological memory and optimal
anti-tumor immunity.

This study has been transitioned to CTIS with ID 2024-517922-24-00 check the CTIS register for the current data.

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).
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


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

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
- WT1 specific T cell responses in bone marrow within the first year post
vaccination
- Early cost-effectiveness of DC vaccination using quality of life data,
utility data and hospital costs. Compare with historic 2015-2023 cohort data of
transplanted AML pts

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 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: theoretically rejection of donor graft
may be 'triggered'. From historical data we have learned that at 8 weeks after
transplantation (date of first vaccination) donor chimerism in T and non-T
cells is 100% in all patients (n=15). This suggests that this 'theoretical"
risk is very low. Nevertheless we will monitor for this.

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