TREATMENT WITH CMV PP65 SPECIFIC T CELLS GENERATED BY USE OF A CMV PP65 PROTEIN-SPANNING PEPTIDE POOL IN PATIENTS WITH CMV REACTIVATION OR CMV DISEASE AFTER ALLOGENEIC STEM CELL TRANSPLANTATION

In immunocompromised recipients of allogeneic stem cell transplantation
(alloSCT), cytomegalovirus (CMV) reactivation can cause serious disease due to
absence of adequate CMV-specific T cells. After alloSCT, pre-emptive treatment
with antiviral therapy in patients with a positive CMV DNA load is usually
performed to prevent CMV disease. However, pharmacological treatment of CMV
reactivation is limited by toxicity and not sufficient for long-term anti-viral
control. Adoptive transfer of selected CMV-specific T cells is safe and can
result in clearance of CMV DNA load. However, the current method is restricted
to certain human leukocyte antigen (HLA)-type of the patient/donor (HLA-A02 of
HLA-B07), results in selection of CD8+ T cells only and is time consuming. In
this study we will use a new method using a pool of overlapping 15-mer peptides
for CMV pp65 to generate CMV-specific CD4+ and CD8+ donor T-cells regardless of
the HLA-type, which makes it applicable to all patients with a CMV seropositive
donor.

• To assess the feasibility, tolerability and safety of administration of donor
or patient derived CMV pp65-specific T cells in patients with CMV reactivation
or CMV disease after alloSCT.
• To determine the presence of CMV specific T cells at different time points
after infusion of CMV pp65-specific T cells.
• To evaluate whether administration of CMV pp65-specific T cells in patients
with persistent CMV reactivation or CMV disease after alloSCT leads to complete
or partial responses.

This is an open-label non-randomized phase I/II feasibility study to treat
patients with persistent CMV reactivation or CMV disease after alloSCT with
administration of CMV pp65-specific T cells generated by use of a CMV pp65
protein-spanning peptide pool.
Patients after alloSCT with a CMV seropositive donor will be monitored weekly
for CMV reactivation using PCR for the detection of CMV DNA. In case of CMV
reactivation (defined as CMV DNA load >1000 cp/ml) patients will be treated
with antiviral therapy according to standard protocols.
For patients with CMV reactivation who fail antiviral therapy (defined as CMV
reactivation treatment failure: persistent CMV DNA load of more than 1000 cp/ml
or CMV disease after 2 weeks of adequate treatment with antiviral therapy or
relapse of CMV DNA load of more than 1000 cp/ml within 4 weeks after adequate
treatment with antiviral therapy or contraindication for treatment with
antiviral therapy at the discretion of the physician) or develop CMV disease
(organ dysfunction (pneumonitis, enteritis, retinitis, encephalitis, hepatitis,
and bone marrow suppression) due to CMV infection), CMV pp65-specific CD4+ and
CD8+ T cells will be generated from donor PBMC by overnight in vitro
stimulation with CMV pp65 peptide pools. CMV-specific CD4+ and CD8+ T cells
will be isolated based on their IFNg production and administered to the patient
directly after quality control. If alloSCT was performed using CD34 positive
cell selection and the CD34 negative subfraction has been cryopreserved at a
GMP facility, this fraction can also be used for selection of CMV-specific T
cells. Antiviral therapy will be continued after infusion of CMV pp65-specific
T cells according to standard antiviral treatment protocols at the discretion
of the physician.
In case of ongoing CMV reactivation or CMV disease the infusion of CMV
pp65-specific T cells may be repeated 2 times with at least 4 weeks interval.
The patient will be monitored for adverse events and for effect on CMV DNA
load. Follow-up of patients will be performed until 6 months after infusion of
CMV pp65-specific T cells or until subsequent DLI, whichever comes first.

Infusion of CMV pp65-specific T cells

Patient will be hospitalized for administration of the T cells.
During or shortly after infusion of CMV pp65-specific T cells patients may
experience mild side effects like fever and chills. These symptoms respond well
to aminocetophen.
If no side effects occur, patients will go home the same day.
Normally, blood tests will be done once a week. In this study two extra blood
tests will be done in the week after administration of CMV pp65-specific T
cells. Thereafter, during 8 weeks blood tests will be done once a week and
thereafter once a month for 4 more months. Blood tests will be combined with
standard blood tests done after allogeneic stem cell transplantation.
A few weeks after infusion of the cells graft versus host disease can develop.
The chance of developing this side effect is less than after infusion of non
specific cultured donor lymphocytes.