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- Thank you so much for giving me the opportunity
to update you on our Gene Therapy study for X-linked SCID.
Before I start, I want to highlight that it's effort
which involves multiple groups, including at UCSF,
which is spearheaded by Morton and Jennifer Puck,
and then at our institution in particular Ewelina Mamcarz.
X-linked SCID is a profound immunodeficiency,
also known as "bubble boy disease",
and infants normally succumb to severe infections
within the first year of life.
The only curative option currently
is a bone marrow transplant,
however, over the last 20 years,
Gene Therapy approaches also have been explored.
In particular, retroviral vectors have been used
and while they were successful
to correct part of the immunodeficiency
also side effects were noted in the form of leukemias
in subset of treated patients.
The late Brian Sorrentino at St. Jude
developed a new lentiviral vector,
with enhanced safety features,
having insulators at both ends of the vector.
And initially had conducted a study in older patients
together with Harry Malik at any age,
and had shown some initial safety as well as efficacy.
This then led to the current study in which newly diagnosed
patient with X SCID are treated.
We take marrow from these patients, in the laboratory.
The stem cells are then,
genetically modified with a lentiviral vector
and then patients receive low dose chemotherapy
before the genetically modified stem cells
are infused into the patient.
Up to now, we have infused 16 patients on this protocol,
their age vary between two months to 14 months.
And the majority of patients had medical problems,
which were in line with the underlying diagnosis
of X-linked SCID.
We were successful in generating cell products
for all of these patients
and the mean vector copy number
of the infused product range
between 0.16 to 1.74 copies per cell.
As mentioned, the patient received low dose busulfan,
which was overall very well tolerated.
And we only observed very mild side effect
in three of the 16 patients.
Importantly, none of the patient required
any blood product transfusion,
although, we observed the transient decline of neutrophils
as well as their platelet count.
So then, we wanted to ask three main questions.
Do patients develop functional T cells and B cells?
Is our gene therapy approach durable and safe?
And, do patients benefit from it?
First, we looked at the development of normal T cells.
And as you can see here,
all patients developed high levels of T cells
except patients number one,
and they, not only developed normal T cells,
but if you look closely,
they are also developed so-called naive T cells,
which is very important for a normal function immune system.
Patients also developed T-cells that had left the thymus,
again, that is very important to make functional T cells,
and reassuringly, these T cells,
now responded to PHA as showing,
on the VCN that they've generated
functional T cells within these patients.
If you look at B cells,
we used the production of antibodies,
which B cells normally do as a surrogate marker.
And as you can see the patient's B cells
started to produce IGA or IGM within a year,
after gene therapy and more importantly,
they also responded to vaccines like normal children.
If you now look at the vector copy number,
in the detected T cells and K cells and B cells,
you will notice that we can readily detect,
genetically modified cells longterm in this patient.
And while there is a little bit fluctuation over time,
the level is actually very constant
for each individual patient.
In addition, we could also detect
genetically modified myeloid cells,
and we also were able to detect genetically modified cells
longterm in bone marrow samples.
If you look a little bit more closer at gene marking,
you realize that there is actually a higher group
and a lower group for T cells and K cells and B cells.
And this really correlates with the number of VCN
in the infused graft.
Children who got graft with low VCN
tend to have lower VCN in their T cells
and K cells and B cells,
whereas children who have high VCN have higher levels.
The question of course,
is does it have any functional consequence?
And fortunately it does not.
If you look here, again, shows the VCN per T cell number,
but if you now look at the T cell count of this patient,
regardless if say I have gotten below or a high VCN graft,
they still develop normal T cells.
In addition to normal T cells, if you now, zoom in,
in the first year, it might be,
that higher VCN graft results,
in the faster T cell reconstitution.
But that is really not the case,
because if you look here regardless of getting,
low or high VCN graphs, this patient developed
or had to same kinetics of a T cell recovery.
If you now look a little bit closer within the genome,
where our lentivirus integrated,
we found a very consistent pattern.
And just to orient you, normally the genome
is presented in a circle where you have,
here's the X chromosomes, Y chromosome,
and then it goes from one all the way around to 22.
And you observed these peaks,
which are very consistent across NK cells,
Myeloid B and T cells.
And if you do a correlative analysis
of all the integration sites,
you will notice that the integration sites overlap
between all these lineages,
indicating that, this our gene therapy approach,
in the end, genetically-modified very,
very early hematopoietic progenitor
or hematopoietic stem cells.
In regards to safety,
I just want to highlight one feature, again,
showing here a chromosome veal and highlighting
consistent integration sites across patients.
So we used the stature now, and looked
in the literature at other studies,
and reassuringly, we find the same integration pattern,
as reported by others, here's chromosomes three
here's chromosome three here's chromosome 11,
here is chromosome 11, highlighting,
that in these very young patients
who receive genetically modified product,
the integration site pattern is exactly the same,
like in older patients who had no side effects
with this type of therapies.
In regards to clinical outcome,
all our patients are doing very well.
And I sorted some again for you,
into the low and high VCN group.
Again, there is no difference in clinical outcome.
All these patients did very well
except for patient number one,
who needed a gene therapy boost one year
after his original infusion,
but since then has done very well.
So in conclusion, our lentiviral vector,
in combination with low dose exposure busulfan
is well tolerated and results in development
of a functional normal immune system.
So far, we have not observed evidence
of malignant transformation.
And we believe that our approach
presents a promising alternative to current therapies.
And of course, our study is ongoing
to determine longterm safety, as well as sustained efficacy.
With this, I want to close and I would like to thank again,
all our collaborators and also in particular CIRM
for supporting this clinical study.
Thank you so much for your attention.
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