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- Hi, I'm Matt Spear, the Chief Medical Officer
at Poseida Therapeutics.
We're a cell and gene therapy company
located in San Diego, California.
Poseida has developed a broad portfolio
of cell and gene therapy technologies,
particularly transposon-based gene transfer,
such as the Super piggyBac system,
and Cas-CLOVER, a novel gene-editing system.
The piggyBac system for gene transfer is unique
in that, instead of using virus to put new genes into cells,
it uses a transposon,
which is a plasmid that carries a cargo,
i.e. the gene to be transferred into cells,
that is cut out by an enzyme called a transposase,
and pasted into the genome,
to express the new gene in the target cells.
This has particular advantages over viruses
and the ability to carry very large numbers of genes,
i.e. a large cargo capacity,
and preferential favoritism for a number of cell types,
such as T stem cell memory cells, or TSCM.
The Cas-CLOVER gene-editing system
is a novel gene-editing system,
which is similar to CRISPR and Zinc Fingers combined.
It uses two guide RNAs
to bring together the dCas9 protein,
along with a Clo51 endonuclease,
to execute the cleavage site
that is targeted to be edited in the gene.
This has the advantage of having a very low
to no off-target editing
because of the utilization of two guide RNAs.
Also, it has the ability to edit resting T cells,
a particular utility in creating CAR-T cells.
We have used this technology to create a broad portfolio
of potential CAR-T and gene therapy products,
particularly focusing on CAR-T cells, at the beginning.
As a reminder, CAR-T cells are T cells
that are been modified with the insertion of a gene
for a CAR, or chimeric antigen receptor,
that targets the T cells towards cancer.
It started out with autologous CAR-T cells.
These are T cells that are taken from an individual patient,
and then modified with the piggyBac transposon system
to carry a CAR, to target these T cells
to cancers such as multiple myeloma and prostate cancer.
Subsequently, using gene-editing system,
we have been able to create allogeneic CAR-T cells,
where one donor can provide T cells to multiple patients.
We're following this on
with a number of gene therapy products
to treat inborn errors of metabolism,
such as OTC, or ornithine transcarbamylase deficiency.
To go into a bit more detail, as to what TSCM,
or T stem cell memory T cells are,
T cells are infection or cancer-fighting cells in the body.
They originate from memory cells,
which may stay in the body for a long period of time,
and then differentiate into effector cells,
which actually do the work of killing infections,
such as viruses or tumor cells.
So you can see why it would be useful to have a CAR-T cell
that originates from a TSCM,
and stays in the body for a long period of time.
You could also imagine where utilizing TSCM T-cells
to create CAR-T cells could be particularly useful
in the treatment of solid tumors.
In that, as a T cell differentiates
into multiple waves of effector T cells,
it could continually eat into a solid tumor.
As I mentioned earlier, Poseida got started
creating autologous CAR-T cells, targeting multiple myeloma.
In particular, P-BCMA-101,
which targets the myeloma-tumor-associated antigen, BCMA.
Myeloma, as you know, is a common blood cancer
that affects many patients in the United States every year.
BCMA is an antigen expressed
on almost all multiple myeloma cells.
Poseida developed the CAR-T cells targeting BCMA
for the treatment of multiple myeloma several years ago,
initiated a clinical trial in 2017,
and has escalated, through multiple cohorts,
multiple dose levels, and was awarded an RMAT status
by the FDA, based off of the results of this study.
This is a description of the study,
a very typical, first-in-man cancer study,
utilizing CAR-T cells.
The study has been conducted
at a large number of academic institutions,
particularly a significant number of institutions
that are CIRM Alpha Stem Cell Center institutions
in California.
The protocol was supported in part by CIRM.
And this allowed us to begin this protocol several years ago
to start treating patients with this new CAR-T cell therapy.
The results of the clinical trial
have been quite good to date.
Cytokine Release Syndrome,
which is a common toxicity associated with CAR-T cells,
has been relatively low,
and response rates have been quite good.
Poseida next moved on to targeting PSMA
for the treatment of prostate cancer
with autologous CAR-T cells called P-PSMA-101.
Like BCMA, PSMA is expressed
on prostate cancer cells broadly.
Prostate cancer, as you know,
affects many men in the United States.
And many of those patients will go on
to develop metastatic castrate-resistant prostate cancer,
failing all prior therapies.
And thus, there's a high unmet medical need
for new therapies such as this.
In this case, the CAR I mentioned earlier
was created to target PSMA instead of BCMA.
That's prostate cancer cells.
Thus far, this has been tested in mice,
having a model of prostate cancer called LNCaP.
Quite successfully, you can see
that the P-PSMA-101 CAR-T cells
eliminated tumors in these mice,
on the right-hand side of this graph.
Recently, we initiated a clinical trial
with P-PSMA-101, in patients
with metastatic castrate-resistant prostate cancer.
Again, the studies leading up to this trial
were funded in part by CIRM.
And there are a number of CIRM sites,
Alpha Stem Cell Center sites,
involved in the conduct of the clinical trial.
The next frontier in the CAR-T cell space
is allogeneic CAR-T cells.
These are CAR-T cells
that have had their MHC class one antigen
and TCR removed, so that one donor
can create CAR-T cells to treat many patients,
as opposed to each donor, each patient,
having to have their own T cells manufactured
to treat themselves.
And you could imagine where this could bring the therapy
to patients much quicker, with much more reproducible
and consistent quality of CAR-T cells.
So Poseida is using its transposon-based technology
to, again, place the CARs, targeting various antigens,
but starting with BCMA again, into donors' T cells,
but also using the Cas-CLOVER gene-editing system
to remove the TCR and MHC class one antigens
to prevent the CAR-T cells from being rejected
by the patient they are transfused into,
as well as eliminating the TCR,
to avoid a reaction against that patient's normal cells
by the CAR-T cells.
There's another novel technology Poseida has developed
to help create these allogeneic CAR-T cells,
called a Booster Technology,
which allows far more doses of CAR-T cells
to be produced with a single donor's T cells.
These CAR-T cells, allogeneic CAR-T cells now,
targeting BCMA, have been tested
in a multiple myeloma preclinical model,
and likewise demonstrated elimination of tumors
in that multiple myeloma mouse model.
And we hope to bring this into a clinical trial
in the near future.
There are a number of other CAR-T programs
Poseida is currently working on,
targeting other tumor-associated antigens
to treat other types of cancer,
such as MUC1C, which is a unique antigen,
which is preferentially expressed
in cancer cells of epithelial origin.
So this is many common types of cancer,
breast cancer, colorectal cancer,
esophageal cancer, gastric cancer, and others.
MUC1 is normally expressed in many cells in the body,
but MUC1C, which these new CAR-T cells target,
is selectively expressed in tumors.
And you can see below,
where there is significant specific antitumor activity,
in vitro, for a number of these tumor types.
And as we've seen in prior slides,
these CAR-T cells also eliminate those tumor types
in mouse models, in particular here,
triple-negative breast cancer and ovarian cancer.
The last thing I want to highlight
is the ability of the transposon technology
to create multi CARs.
Because of the large cargo capacity,
or the large number of genes a transposon can carry,
we can put many different CARs into a single CAR-T cell.
This is an example of four different CARs,
or four different targets,
being put into a single cell, a single CAR-T cell,
and those CAR-T cells being able to subsequently
target multiple different tumor types
expressing those different antigens.
At Poseida, we hope to develop these
into multi-targeted, or bi-targeted CAR-T cells,
dual CAR-T cells, in the next several years.
So overall, we've been very excited
with what we have accomplished thus far,
with CIRM's funding, and CIRM's assistance,
and partnership with CIRM,
and look forward to upcoming potential advantages
and advances in the field,
using this novel technology platform, thank you.
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