Transcript Diapositiva 1

Specificità della clinica: la
ricostituzione immunologica, la
GVHD e le complicanze infettive
F. Narni
No immune suppression after transplantation!!!
• Delayed immune reconstitution is
the main limitation of T-cell
depleted Haplo-HCT
1st
2nd
Add-back of donor T cells
risk of severe GvHD
6,0E+08
5,0E+08
4,00E+08
4,0E+08
3,0E+08
CD3
2,0E+08
1,0E+08
0,0E+00
1,00E+04
PBSC
T-depl,
1,00E+07
DLI
TK cells = donor lymphocytes
genetically engineered to express
HSV-thymidine kinase gene
GMP lab
Selection
Transduction
Drug product
HSV-thymidine kinase gene =
suicide gene: once integrated
into donor lymphocytes DNA, makes
them sensitive to Ganciclovir (GCV).
GVHD
ganciclovir administration
GCV is phosphorylated by
HSV thymidine kinase
blockage of DNA synthesis
death of proliferating cells.
Objective:
Infectious adverse events
GVHD
Ganciclovir
• Any of the following conditions:
•AML and ALL in 1st CR at high-risk of
relapse based on negative
prognostic factors
•AML and ALL in 2nd or subsequent
CR
•Secondary AML in CR
• Absence of fully HLA matched family or
unrelated donor
• Phase III study, Double arm, open
label, randomized (3:1)
• Multicentre, Multinational
• 152 patients to be enrolled (114 in
the experimental arm and 38 in the
control arm)
in patients of both arm A and B
The graft composition should
be adjusted to contain a
minimum of 7x106 CD34+/kg
stem cells
and a dose of 1x104 CD3+/kg
lymphocytes
Experimental arm
Weekly Immunophenotype
two consecutive findings of circulating CD3+
cells < 100/μl:
1st Infusion between day + 21 to days +49 after HCT (1 x
107 cells/kg)
2nd Infusion +30 days after 1st INFUSION (1 x 107 cells/kg)
3rd Infusion +30 days after 2nd INFUSION (1 x 107 cells/kg)
4th Infusion +30 days after 3rd INFUSION (1 x 107 cells/kg)
In case of GvHD
the patients will be treated with
ganciclovir at a dose of 10 mg/Kg/day i.v.
divided into 2 administrations
or
val-ganciclovir 900 mg bid p.o. for 14 days
Primary endpoint: Disease-free survival
Secondary endpoints
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Overall Survival (OS)
Non-relapse mortality (NRM)
Time to immune reconstitution (IR)
Engraftment rate
Cumulative incidence of aGvHD
Cumulative incidence of extensive cGvHD
Cumulative incidence of relapse (CIR)
despite the preferential integration of the retroviral vector
within or in the proximity of transcriptionally active genes,
transduced T cell population maintained a stable gene profile
expression, phenotype and biological functions.
A comparison of the integration site in transduced T cells
before and after infusion showed that vector integration within
genes involved in cell cycle control or in other physiological T
cellfunctions were counter-selected in vivo.
Furthermore, no clonal selection or expansion could be
observed during the follow up. Therefore, the results obtained
clearly point out that retroviral integration in SFCMM-3
transduced T cells are not associated to a measurable risk of
insertional oncogenesis.
Long term follow-up period of 15 years
For the first 5 years a general health
evaluation with a physician and collection
of blood samples (about 10 ml) on an
annual basis, for detection of late clinical
outcomes suggestive of retroviral disease,
including new/recurrent malignancies,
neurologic disorders, hematologic
disorders, autoimmune disorders,
unexpected medical problems and
hospitalizations
For the subsequent 10 years, only a specific
questionnaire will be filled in by the
patients