Vaccination with minor histocompatibility antigen-loaded donor DC vaccines to boost graft-versus-tumor immunity after allogeneic stem cell transplantation (a phase I study)

Allogeneic stem cell transplantation (allo-SCT) is a potent treatment and
sometimes the only curative treatment for aggressive hematological
malignancies. The therapeutic efficacy is attributed to the graft-versus-tumor
(GVT) response, during which donor-derived CD8+ T cells become activated by
recipient minor histocompatibility antigens (MiHA) presented on dendritic cells
(DC). Consequently, these alloreactive donor T cells clonally expand, acquire
effector functions and kill MiHA-positive malignant cells. However, in a
substantial number of patients persistence and recurrence of malignant disease
is observed, indicating that insufficient GVT immunity is induced. This is
reflected by our observation that not all patients develop a productive CD8 T
cell response towards mismatched MiHA between the recipient and donor. A
promising strategy to induce or boost GVT immune responses is pre-emptive or
therapeutic vaccination with ex vivo-generated donor DC loaded with MiHA that
are exclusively expressed by recipient hematotopoietic cells and their
malignant counterparts. In contrast to pre-emptive donor lymphocyte infusion
(DLI) with polyclonal donor T cells, this MiHA-DC vaccination approach has less
risk of inducing GVHD and the potency to induce more efficient GVT-associated T
cell immunity.

The primary objectives of our study are to evaluate safety, toxicity and
capability of inducing T cell responses of vaccination with, monocyte-derived
donor DC electroporated with mRNA encoding hematopoietic-restricted MiHA in
patients who had undergone allo-SCT with stem cells from HLA-matched,
MiHA-mismatched donor. The secondary objective is to evaluate the clinical
effect of vaccination in case of detectable minimal residual disease and mixed
chimerism.

This is a phase I/II study in a series of 10 allo-SCT recipients. Eligible
patients include MiHA-mismatched patients who do not develop aGVHD * grade 2 or
extensive cGVHD after stopping cyclosporine A, and have no or limited
MiHA-specific T cell response (defined by *1.0% of total CD8+ T cells). These
eligible patients will receive pre-emptive MiHA-DC vaccination.

Eligible patients will receive one cycle of donor DC vaccination consisting of
maximal 3 immunizations, given at 2 week intervals. MiHA mRNA-electroporated
donor DC will be infused intravenously (2.5x105/kg body weight).

Participating patients will visit the outpatient clinic weekly or two-weekly
for standard physical examination and blood sampling from the first DC
vaccination until 4 and 12 weeks after vaccination, respectively. For
follow-up, peripheral blood will be collected from patients pre-study, at day
0, 7, 14, 21, 28, 42, 63 and 84 during and after DC vaccinations. The total
amount of blood that will be taken for study purposes will be maximally 282 ml
in a three month period. Two extra bone marrow aspirations will be performed
(day 42 and 84 after first DC vaccination). Theoretically, the risk of MiHA-DC
vaccination is the development of a strong T cell response inducing GVHD or an
anaphylactic reaction. However, as the MiHA HA-1, LRH-1 or ARHGDIB are
expressed only by hematopoietic cells we do not expect severe acute GVHD.
Furthermore, because CD8+ T cell responses against these
hematopoietic-restricted MiHA occur in allo-SCT patients by nature, we do not
expect a systemic anaphylactic reaction. Indeed in a previous
post-transplantation vaccination study with recipient-derived DCs expressing
endogenous MiHA, the toxicity was limited to low-grade fever and chills, but
none of the patients developed GVHD (Levenga et al. BBMT 2010). Finally, when
MiHA-DC vaccination indeed yields a productive immune response, with increasing
donor chimerism and/or reducing residual disease, there is no need for a DLI
thereby decreasing the risk of acute GVHD. In addition, DC-induced
MiHA-specific CD8+ T cell responses could be associated with a lower relapse
rate.