Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage
biopharmaceutical company dedicated to the development of
programmed cellular immunotherapies for patients with cancer, today
announced the publication of preclinical study results
demonstrating the successful generation, durable anti-tumor
response, and functional persistence of TCR-CAR+ iPSC-derived CD8αβ
T cells from induced pluripotent stem cells (iPSCs). The CD8αβ T
cells were derived from a single engineered iPSC integrating a
novel chimeric antigen receptor (CAR) transgene into the T-cell
receptor alpha constant (TRAC) locus, ensuring complete bi-allelic
disruption of T-cell receptor (TCR) expression and promoting
uniform CAR expression. The discoveries were made under a
multi-year research collaboration between the Company and Memorial
Sloan Kettering Cancer Center (MSK) led by Michel Sadelain, M.D.,
Ph.D., Director, Center for Cell Engineering and Head, Gene
Expression and Gene Transfer Laboratory, and were published this
week in Nature Biomedical Engineering.
“Scientists have previously differentiated induced pluripotent
stem cells to form CAR T cells, however, it was observed that
premature αβTCR or constitutive CAR expression resulted in the
derivation of innate-like T cells that do not acquire the phenotype
nor exhibit the function of conventional CD8αβ T cells,” said Dr.
Sadelain. “Our published findings are the first to show the
generation of iPSC-derived CD8αβ CAR T cells lacking a TCR, where
timed and calibrated expression of the CAR in place of the TCR
successfully drove T-cell maturation and promoted the acquisition
of a transcriptional and functional profile more closely resembling
that of natural CD8αβ T cells.”
The mass production of TCR-CAR+ CD8αβ T cells from master
engineered iPSC lines is a promising approach for development of
off-the-shelf, cell-based cancer immunotherapies. Through a
systematic assessment of factors that affect T-cell lineage
commitment and induce adaptive T-cell formation, the researchers
discovered that integrating the CAR construct into the TRAC locus
delayed its expression and drove T-cell lineage commitment, and
that regulation of CAR signaling strength promoted the generation
of CD4+CD8+ double-positive cells mimicking thymic development in
the absence of a TCR. Subsequent stimulation of the CAR matured the
double-positive population into single-positive CD8αβ T cells with
a phenotype highly correlated with peripheral blood CD8αβ effector
T cells and distinct from γδ T cells and natural killer cells.
Preclinical studies showed that iPSC-derived TCR-CAR+ CD8αβ T cells
were able to repeatedly lyse tumor cells in vitro and durably
control leukemia in vivo, with persistence in the bone marrow,
spleen, and blood, in a systemic NALM6 leukemia model.
“These published findings continue to support our unique ability
to generate TCR-CAR+ CD8αβ T cells from master engineered iPSC
lines that exhibit a phenotypic profile and anti-tumor activity
comparable to healthy donor-derived peripheral blood CAR T cells in
preclinical model systems,” said Scott Wolchko, President and Chief
Executive Officer of Fate Therapeutics. “We believe our
off-the-shelf, iPSC-derived CAR T cell programs overcome the
numerous challenges associated with the manufacture, consistency,
and reach of autologous and allogeneic CAR T cells, and we look
forward to sharing initial clinical data from our landmark Phase 1
study of FT819 later this year.”
The Company is conducting a multicenter Phase 1 study of FT819,
the first T-cell therapy manufactured from a clonal master iPSC
line to undergo clinical investigation. The product candidate’s
clonal engineered master iPSC line is created from a single iPSC
that has a novel CD19-targeted 1XX CAR construct integrated into
the TRAC locus, ensuring complete bi-allelic disruption of TCR
expression to prevent graft-versus-host disease and promoting
uniform CAR expression for enhanced anti-tumor activity. Dose
escalation is currently ongoing in single-dose and multi-dose
escalation cohorts for relapsed / refractory B-cell
malignancies.
Pursuant to a license agreement with MSK, Fate Therapeutics has
an exclusive license for all human therapeutic use to U.S. Patent
No. 10,370,452, which covers compositions and uses of effector T
cells expressing a CAR, where such T cells are derived from a
pluripotent stem cell including an iPSC. In addition to the patent
rights licensed from MSK, the Company owns an extensive
intellectual property portfolio that broadly covers compositions
and methods for the genome editing of iPSCs using CRISPR and other
nucleases, including the use of CRISPR to insert a CAR in the TRAC
locus for endogenous transcriptional control.
Fate Therapeutics has licensed intellectual
property from MSK on which Dr. Sadelain is
an inventor. As a result of the licensing arrangement,
MSK has financial interests related to Fate Therapeutics.
About Fate Therapeutics’ iPSC Product
PlatformThe Company’s proprietary induced pluripotent stem
cell (iPSC) product platform enables mass production of
off-the-shelf, engineered, homogeneous cell products that are
designed to be administered with multiple doses to deliver more
effective pharmacologic activity, including in combination with
other cancer treatments. Human iPSCs possess the unique dual
properties of unlimited self-renewal and differentiation potential
into all cell types of the body. The Company’s first-of-kind
approach involves engineering human iPSCs in a one-time genetic
modification event and selecting a single engineered iPSC for
maintenance as a clonal master iPSC line. Analogous to master cell
lines used to manufacture biopharmaceutical drug products such as
monoclonal antibodies, clonal master iPSC lines are a renewable
source for manufacturing cell therapy products which are
well-defined and uniform in composition, can be mass produced at
significant scale in a cost-effective manner, and can be delivered
off-the-shelf for patient treatment. As a result, the Company’s
platform is uniquely designed to overcome numerous limitations
associated with the production of cell therapies using patient- or
donor-sourced cells, which is logistically complex and expensive
and is subject to batch-to-batch and cell-to-cell variability that
can affect clinical safety and efficacy. Fate Therapeutics’ iPSC
product platform is supported by an intellectual property portfolio
of over 350 issued patents and 150 pending patent applications.
About FT819FT819 is an investigational,
universal, off-the-shelf, T-cell receptor (TCR)-less CD19 chimeric
antigen receptor (CAR) T-cell cancer immunotherapy derived from a
clonal master induced pluripotent stem cell (iPSC) line, which is
engineered with the following features designed to improve the
safety and efficacy of CAR19 T-cell therapy: a novel 1XX CAR
signaling domain, which has been shown to extend T-cell effector
function without eliciting exhaustion; integration of the CAR19
transgene directly into the T-cell receptor alpha constant (TRAC)
locus, which has been shown to promote uniform CAR19 expression and
enhanced T-cell potency; and complete bi-allelic disruption of TCR
expression for the prevention of graft-versus-host disease. FT819
demonstrated antigen-specific cytolytic activity in vitro against
CD19-expressing leukemia and lymphoma cell lines comparable to that
of primary CAR T cells, and persisted and maintained tumor
clearance in the bone marrow in an in vivo disseminated xenograft
model of lymphoblastic leukemia. FT819 is being investigated in a
multicenter Phase 1 clinical trial for the treatment of relapsed /
refractory B-cell malignancies, including B-cell lymphoma, chronic
lymphocytic leukemia, and acute lymphoblastic leukemia
(NCT04629729).
About Fate Therapeutics, Inc.Fate Therapeutics
is a clinical-stage biopharmaceutical company dedicated to the
development of first-in-class cellular immunotherapies for patients
with cancer. The Company has established a leadership position in
the clinical development and manufacture of universal,
off-the-shelf cell products using its proprietary induced
pluripotent stem cell (iPSC) product platform. The Company’s
immuno-oncology pipeline includes off-the-shelf, iPSC-derived
natural killer (NK) cell and T-cell product candidates, which are
designed to synergize with well-established cancer therapies,
including immune checkpoint inhibitors and monoclonal antibodies,
and to target tumor-associated antigens using chimeric antigen
receptors (CARs). Fate Therapeutics is headquartered in San Diego,
CA. For more information, please visit
www.fatetherapeutics.com.
Forward-Looking StatementsThis release contains
"forward-looking statements" within the meaning of the Private
Securities Litigation Reform Act of 1995 including statements
regarding the advancement of and plans related to the Company's
product candidates, clinical studies and preclinical research and
development programs, the Company’s progress, plans and timelines
for the manufacture and clinical investigation of its product
candidates, the Company’s initiation and continuation of enrollment
in its clinical trials including additional dose cohorts in ongoing
clinical trials of its product candidates, the therapeutic and
market potential of the Company’s product candidates, and the
Company’s clinical development strategy, including for its product
candidate FT819. These and any other forward-looking statements in
this release are based on management's current expectations of
future events and are subject to a number of risks and
uncertainties that could cause actual results to differ materially
and adversely from those set forth in or implied by such
forward-looking statements. These risks and uncertainties include,
but are not limited to, the risk that the Company’s product
candidates may not demonstrate the requisite safety or efficacy to
warrant further development or to achieve regulatory approval, the
risk that results observed in prior studies of the Company’s
product candidates, including preclinical studies and clinical
trials, will not be observed in ongoing or future studies involving
these product candidates, the risk of a delay or difficulties in
the manufacturing of the Company’s product candidates or in the
initiation and conduct of, or enrollment of patients in, any
clinical trials, the risk that the Company may cease or delay
preclinical or clinical development of any of its product
candidates for a variety of reasons (including requirements that
may be imposed by regulatory authorities on the initiation or
conduct of clinical trials, changes in the therapeutic, regulatory,
or competitive landscape for which the Company’s product candidates
are being developed, the amount and type of data to be generated or
otherwise to support regulatory approval, difficulties or delays in
patient enrollment and continuation in the Company’s ongoing and
planned clinical trials, difficulties in manufacturing or supplying
the Company’s product candidates for clinical testing, and any
adverse events or other negative results that may be observed
during preclinical or clinical development), the risk that results
observed in preclinical studies of FT819 may not be replicated in
ongoing or future clinical trials, and the risk that FT819 may not
produce therapeutic benefits or may cause other unanticipated
adverse effects. For a discussion of other risks and uncertainties,
and other important factors, any of which could cause the Company’s
actual results to differ from those contained in the
forward-looking statements, see the risks and uncertainties
detailed in the Company’s periodic filings with the Securities and
Exchange Commission, including but not limited to the Company’s
most recently filed periodic report, and from time to time in the
Company’s press releases and other investor communications. Fate
Therapeutics is providing the information in this release as of
this date and does not undertake any obligation to update any
forward-looking statements contained in this release as a result of
new information, future events or otherwise.
Contact:Christina TartagliaStern Investor
Relations, Inc.212.362.1200christina@sternir.com
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