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- Hi everybody, thank you for having me today.
I'm here to talk to you about neural stem cell targeted
anti-cancer therapies, going from bench to bedside.
And also show you some of the work that CIRM has enabled us
to do through their grant funding.
So stem cells are regenerative.
I'm sure you've heard a lot about that today.
They can regenerate skin, blood, bone, heart nerves.
I showed this cartoon that you can be anything you want
to be when you grow up.
And it's the researcher's goal to push the cells
in the direction that they want.
You can turn these stem cells into heart,
beating heart cells and to nerves into skin tissue.
However, what I looked at the stem cells for
is not regenerative,
but that they are also pathotropic.
What I mean by that is that the stem cells are attracted
to areas of pathology.
And I was a cancer researcher, so I was interested to know,
are they attracted to cancer cells, right?
Cancer cells invade tissue.
They do damage with the stem cells go there.
So just to give you an overview,
a lot of the work being done now by CIRM investigators
and others is stem cell replacement,
their trials on macular degeneration going on now,
where they actually inject the stem cells into the eye
to replace the damaged cells in the eye and restore vision,
remyelination, to remyelinate nerves that are damaged
with spinal cord injury.
So again, stem cells from when you're born, as you develop,
they know how to do all these things and make normal nerves
and normal eye cells and heart tissue.
But when it gets damaged later on,
can you put the stem cells there
and regenerate the tissue
since they knew how to do it when you were developing,
can they do it now or trick the environment into
regenerating the tissue?
So promotion of host tissue regeneration,
we're looking at stroke Parkinson's disease, ALS
cell replacement.
So again, those are all regenerative properties
of stem cells.
What I'm looking at is Patho-tropism,
or in this case, tumor tropism
that the stem cells are in fact attracted
to invading tumor cells.
And if they are, can we localize the treatment only
to the tumor cells and then avoid off target toxic effects?
So what I discovered about wow!
20 years ago is that neural stem cells,
So these are stem cells that have already been committed
to becoming brain cells, different cells in the brain.
So neural stem cells, they have an inherent ability
to track down cancer cells.
So this is not something I did to them.
It was something I observed.
They can cross the blood brain barrier to the brain.
And since they can track down cancer cells,
I'm using them as a delivery vehicle to deliver different
therapeutic payloads directly to the tumor sites.
And in this way, normal tissues are spared
from the toxic side effects and reducing suffering
and improving quality of life.
For example, when a patient gets chemo, intravenously,
the chemo is killing everything that's dividing quickly.
It doesn't distinguish between your tumor cells
and for instance, your hair cells or your bone marrow
or your skin, which is why you get so many side effects,
it's killing everything that's dividing quickly.
In this case, if we can activate the chemotherapy only
at the tumor sites, we would avoid all those other effects.
And that was the goal to improve quality of life.
So early studies that we did,
this is a model where there's a tumor in the brain.
The tumor is the dark red
and a surgeon can go ahead and remove the tumor in the brain
we looked at brain tumors first,
but the surgeon will miss cells that already invaded
into the normal tissue and unlike liver or lung,
you can't remove part of the brain tissue.
So the question is you can remove the tumor,
but how do you get those invading cells without hurting
the rest of the brain?
On the left It shows that the NSCS here, they're dyed blue,
that when we inject the stem cells into a tumor,
they don't just sit there they move,
they love the tumor environment.
They distribute all over the tumor.
Also they cross normal tissue
to follow invading tumor cells.
And in the right panel, we see tumors always are making,
taking over blood vessels to feed itself so it can spread.
And as you can see, the stem cells love
these new blood vessels too.
So it seems like whatever's making the tumor
more aggressive, more invasive is also attracting
these neural stem cells.
So over the years, we've used stem cells as a platform
to target several different anticancer agents
directly to invasive cancer cells.
We've done this in models of glioma,
medullablastoma, metastasis to the brain.
This is an increasing population is over 180,000 new cases,
a year of brain metastasis,
because as our treatments have gotten better systemically,
for example, for lung cancer, breast cancer,
more and more patients are presenting with brain Mets
because a lot of these chemotherapies and drugs
do not cross the blood brain barrier.
So patients are presenting that way now.
Also, if we inject the stem cells intravenously,
they will cry the blood brain barrier
and localized tumor sites.
Finally, and this is a more recent grant
that I'll talk about.
Neural stem cells when they're injected intravenously
or into the abdomen,
they will localize to metastatic cancers
throughout the body, including breast carcinoma,
neuroblastoma, and ovarian cancer.
So these cells will stop at the tumor sites.
They're recognizing something in the tumor vasculature
and they'll penetrate into the tumor.
So again, I didn't do anything to the stem cells
to make them tumor-tropic.
This is what we observed and discovered.
What we're doing is adding a therapeutic payload
to carry it directly to the tumor sites.
So we started with brain tumor therapy
and brain tumor treatment today.
There have been advances in surgery, radiation,
and chemotherapy.
However, despite all those advances,
these tumors are virtually incurable and lethal.
Why? Well, there's no clear boundaries of these tumors
by the time they're diagnosed,
they've already spread away from one primary mass
and one tumor spread away from the main tumor site
that's invasive or metastases.
Again, the chemotherapies do not cross
the blood brain barrier well
about 98% of them don't get through.
And when they do get through there's poor tumor penetration.
So there has not been a significant advance.
The prognosis is about two years from the time of diagnosis
and only six months,
six to eight months from when it recurs.
So what our lab did is we developed a neural stem cell line
for clinical use.
And allogeneic means that we can use this one line
and apply it to many different people,
to all different patients.
Autologous is when they take it from the patient
and give it back to the same patient.
But we were looking for an "off the shelf" product,
something that can be frozen down in vials,
and then used as needed for the different patients.
And we've characterized this,
they're frozen down at City of Hope, a GMP facility,
which is for clinical products,
they're minimally in the immunogenic.
So they don't get rejected very easily.
It's expandable.
So we've engineered this cell line
so that we do not need any tissue.
We do not need to go back to any new characterization.
Every vial of these cells has exactly the same thing.
Now, these stem cells can be modified further
with different therapeutic payloads.
And we were the first to take this to human trials
with an "off the shelf" NSC line
to deliver a therapeutic agent.
And our first therapy was NSC neural stem cell mediated
enzyme prodrug gene therapy.
And this is what I had mentioned
that the stem cells will go to the tumor site,
that we've engineered them to make an enzyme
that does nothing by itself.
But now when you give an inactive prodrug,
and that does cross to the brain,
the enzyme will convert it to the active drug,
the chemotherapeutic only in the area where the tumors are.
So this is stem cells are administered.
They localized to the tumor.
They make their enzyme,
we give an active prodrug.
So now you have localized chemotherapy production
because it's only gonna be made where the stem cells are.
And the stem cells only where the tumor sites are.
Now CIRM gave me an $18 million disease team award
in 2010 to take a brand new NSC treatment
to patients with glioma.
This was how we did it we took stem cells.
We engineered them to make an enzyme
in this case it's called CE.
Then we treat the patient with Irinotecan
and then the stem cell enzyme converted
to a drug called SN-38.
This is 3000 times more potent,
more yeah anticancer effect than Irinotecan alone.
And we're only localizing it to the tumor sites.
So this toxic drug is not going through the whole body
and not affecting doing normal tissues.
It's only being made where the tumor is.
Now, one of the things besides getting to clinical trial,
I think we have one patient and left on this clinical trial
is the funding from CIRM enabled us
to get additional funding based on what we discovered.
And we did get $2 million from NIH
to conduct the clinical trial.
And we also got almost $5 million from NIH to apply
the same treatment that we developed for brain tumor,
the exact same cell product for metastatic neuroblastoma
injected intravenously.
And this will be going to clinical trial hopefully
within the next six months.
So it's just to point out that what CIRM has enabled us
to do and our original proposal has had ramifications
for other tumors and other payloads.
So we did do a phase I, as I said,
we have one patient left dose escalation multi-dose trial.
The patient is come in with recurrent glioma.
The surgeon removes the tumor.
And then the stem cells that are making the CE are injected
into the resection cavity wall
and two centimeters around the wall
is where most of the recurrent tumor happens.
But again, I showed you there's gonna be distant tumor sites
that the surgeon will miss.
And we believe our stem cells migrate
to those distant sites also.
So now you have the stem cells localized to the tumor sites
and we give the Irinotecan drug.
And now we make that SN-38
that powerful chemotherapeutic
only at the tumor sites.
We also have a City of Hope has an alpha clinic,
a storm alpha clinic.
So we leave a catheter in under the skull
if the patient doesn't show,
but that way they can come in every month or every two weeks
to get another dose of stem cells and the drug.
So we can give them repeat treatment rounds.
Our clinical trials so far have demonstrated
that the stem cells are moving to distant tumor sites,
even in the opposite side of the brain.
And they are converting the prodrug
to the act of chemotherapeutics.
So we have proof of concept.
Again, these initial phase I trials are for safety.
They're quite small, but once they're finished,
we can move to phase two larger studies
and increasing dosing.
And then I wanted to just finish with a new translational
grant that we were awarded.
We went to clinical trial with an oncolytic virotherapy,
so the same stem cells,
but now they're making an oncolytic virus.
This virus will infect tumor cells.
It will keep dividing till it bursts the tumor cell open.
And then it will spread to the next tumor cells
and the next tumor cells.
And it should keep amplifying until it hits normal tissue.
This is important because even if the tumor cells
are chemo resistant or radiation resistant, it's effective,
there are many trials with free virus.
Free virus gets neutralized by the immune system .
It doesn't reach the tumor sites well,
and it doesn't penetrate well.
And we also can't give multiple treatment rounds
because of the immune system.
By in casing the virus in the stem cells
and let the stem cells protect it on its way
to the tumor sites.
We can get more of the virus to the tumor site
and we can give multiple rounds of treatment.
So the grant that we have just received in February
is for ovarian cancer.
22,000 women per year are affected,
stage III ovarian cancers
when the tumor cells are in the abdomen,
And many after treatment with cisplatin and paclitaxe,
they become resistant to the chemo.
So we wanted to try this same product
of the oncolytic virus into the ovarian cancer.
And what we have shown so far is that the stem cells here,
they're red and orange, these are tumor sites.
When we inject them and trap dominantly,
they localize to the ovarian tumor sites
to multiple ovarian tumor sites throughout the abdomen.
They're not localizing to normal tissue, kidney or liver.
So there'll be at the tumor sites,
they'll be making their oncolytic virus
they'll infect the tumor cells,
lyse them, release more virus.
And again, we hope to get an amplifying effect
until the tumors are gone.
So this is the $2.8 million CIRM TRAN
and that is to get us to the point of submission
to the FDA for a clinical trial, with this oncolytic virus,
neural stem cells to go into stage III
ovarian cancer patients.
And I just wanna thank CIRM
I wanna thank my lab, who does all the work,
I just get to present it.
And all our clinicians, brain tumor and ovarian cancer.
And again, CIRM has enabled us to go from basic science
to translational, to the clinic.
It's a big team effort,
and it is an expensive effort and we're very grateful
to have gotten funding and to be able to do this.
Thank you so much.
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