Cellectis (the “Company”) (Euronext Growth: ALCLS - NASDAQ: CLLS),
a clinical-stage biotechnology company using its pioneering
gene-editing platform to develop life-saving cell and gene
therapies, showcased preclinical data at an oral presentation and
two poster presentations at the International Society for Cell
& Gene Therapy (ISCT) 29th annual event that took place at the
Paris Convention Center in Paris, France on May 31 - June 3, 2023.
“Our breadth of scientific presence at the 29th
ISCT annual event reflects the type of cutting-edge research our
teams undertake, which we believe is essential to address patients’
unmet medical need. We are proud of the pre-clinical results
presented and remain deeply focused on the development of our
product candidates to deliver breakthrough treatments that could
benefit thousands of patients worldwide,” said André Choulika,
Ph.D., Chief Executive Officer at Cellectis.
Oral Presentation
UCART20x22: allogeneic dual CAR T-cells
for the treatment of B-cell malignancies
Autologous CAR T-cell therapies have shown
outstanding responses in the treatment of selected blood cancers,
predominantly B-cell malignancies. Nevertheless, long term studies
revealed that some patients treated with CD19 or CD22 CAR T-cells
can relapse due to low target antigen expression in tumor cells or
to antigen loss. The therapeutic options after CAR T-cell relapses
are limited, emphasizing the need to develop novel therapies to
improve current survival rates. There is also need for allogeneic
“off-the-shelf” therapies that could be readily available at the
time of treatment decision and overcome limitations of current
autologous approaches.
UCART20x22 is Cellectis’ first dual-targeting,
allogeneic cell therapy product candidate targeting CD20 and CD22,
to address the current challenges in the treatment of B-cell
malignancies.
UCART20x22 features TALEN®-mediated disruptions
of the TRAC gene (to minimize the risk of graft-versus-host
disease) and of the CD52 gene (to permit use of a CD52-directed
monoclonal antibody in patients’ lymphodepletion regimen) to
enhance CAR T engraftment, expansion, and persistence.
Cellectis demonstrates that UCART20x22 displays
robust activity in vitro and in vivo, against targets expressing
heterogeneous levels of CD22 and CD20. We have used in vitro
cytotoxicity assays against different tumor cell lines, showing
strong activity whether these cells express a single antigen (CD20
or CD22) or both antigens simultaneously, as well as IFNg release
in response to antigen specific stimulation.
The oral presentation highlighted the
following preclinical data:
- Robust in vitro and in vivo cytolytic activity against tumors
expressing different antigen combinations.
- Efficient in vitro targeting of primary B-cell Non-Hodgkin
Lymphoma (B-NHL) samples harboring different CD20 and CD22
expression levels, suggesting that UCART20x22 has the potential to
reach a large patient population.
- Dose dependent tumor control in vivo, using batches
manufactured internally, harboring a tumor cell line as well as in
a Patient Derived Xenograft (PDX) model of B-NHL.
Overall, Cellectis provided pre-clinical
proof-of-concept data for a first allogeneic dual CAR T-cell to
overcome current mechanisms of resistance to CAR T-cell therapies
in B-NHL, while providing a potential therapeutic alternative to
CD19 targeting and allowing to reduce the time from treatment
decision to infusion.
UCART20x22 is currently evaluated in the
NATHALI-01 Phase 1/2a clinical study in patients with
relapsed/refractory B-NHL (NCT05607420).
The oral presentation is available on Cellectis’
website:
https://www.cellectis.com/en/investors/scientific-presentations/
Poster Presentations:
Non-viral DNA delivery associated to
TALEN® gene editing leads to highly efficient correction of sickle
cell mutation in long-term repopulating hematopoietic stem
cells
Sickle cell disease stems from a single point
mutation in the HBB gene which results in sickle hemoglobin. For
patients who are not eligible for an allogeneic stem cell
transplantation, nuclease-based gene therapy approaches provide a
relevant therapeutic alternative to restore functional hemoglobin
production.
Cellectis leveraged TALEN® technology to develop
a gene editing process leading to highly efficient HBB gene
correction via homology directed repair, while mitigating potential
risks associated to HBB gene knock-out. Furthermore, we compared
viral (TALEN-V) and non-viral (TALEN-NV) DNA template delivery
strategies in mobilized healthy donor (HD) or non-mobilized
homozygous sickle patient (HbSS) hematopoietic stem and progenitor
cells (HSPCs).
Both strategies led to high and comparable
efficiencies of HBB gene correction in vitro in HD and HbSS,
without affecting viability, purity or clonogenic potential of
corrected HSPCs.
The poster presentation highlighted the
following data:
- TALEN®-mediated engineering
efficiently corrects the mutated HBB gene in clinically relevant
HSPCs and promote phenotype correction in fully mature RBCs.
- Cellectis optimized TALEN® gene
editing process mitigates potential safety challenges by reducing
the frequency of HBB gene inactivation (<10% β-thal cells).
- Non-viral DNA template-mediated HBB
repair mitigates p53 DNA damage response activation, preserves
edited LT-HSCs fitness and enables their efficient engraftment in
vivo using an immunodeficient murin model.
These results show that non-viral DNA delivery
associated to TALEN® gene editing reduces the toxicity usually
observed with viral DNA delivery and allows high levels of HBB gene
correction in long-term repopulating hematopoietic stem cells.
The poster presentation is available on
Cellectis’ website:
https://www.cellectis.com/en/investors/scientific-presentations/
Comprehensive Analysis of the Editing
Window of TALE Base Editors
One of the most recent advances in the genome
editing field has been the addition of the so-called “C-to-T TALE
base editors” (TALE-BE), an innovative platform for cell therapy
that relies on the deamination of cytidines within double strand
DNA, through the formation of an uracil (U) intermediate. These
molecular tools are fusions of a transcription activator-like
effector (TALE) domain for the binding of a specific DNA sequence,
split-DddA deaminase halves that will catalyze the conversion of a
cytosine (C) to a thymine (T) upon reconstitution, and an uracil
glycosylase inhibitor (UGI).
Cellectis aimed to systematically investigate
the influence of the sequence context surrounding the targeted
Cytosine on TALE-BE C to T conversion efficiency.
Recently we developed a strategy that allowed us
to comprehensively characterize editing efficiencies in function of
the TC position within the TALE-BE editing windows. This method is
specifically taking advantage of the highly precise and efficient
TALEN mediated ssODN knock-in in primary T cells, allowing to focus
on how target composition and spacer variations can affect TALE-BE
activity/efficiency.
The poster presentation highlighted the
following data:
- Determined optimal spacer length (13/15 bp) for highly
efficient TALE-BE for both C40/C40 and C11/C11 scaffolds.
- Determined optimal common sequence context for high editing
rates.
- Determined that editing efficiency of the C11/C11 scaffold is
highly dependent on Cytosine position requirements, resulting in
more stringent activity in a context of 15 bp spacer size and
decreasing the effects of bystander editing.
Overall, we believe that the knowledge obtained
will allow to better design efficient TALE-BE while improving the
specificity profiles of this innovative editing platform.
The poster presentation is available on
Cellectis’ website:
https://www.cellectis.com/en/investors/scientific-presentations/
About Cellectis
Cellectis is a clinical-stage biotechnology
company using its pioneering gene-editing platform to develop
life-saving cell and gene therapies. Cellectis utilizes an
allogeneic approach for CAR-T immunotherapies in oncology,
pioneering the concept of off-the-shelf and ready-to-use
gene-edited CAR T-cells to treat cancer patients, and a platform to
make therapeutic gene editing in hemopoietic stem cells for various
diseases. As a clinical-stage biopharmaceutical company with over
23 years of experience and expertise in gene editing, Cellectis is
developing life-changing product candidates utilizing TALEN®, its
gene editing technology, and PulseAgile, its pioneering
electroporation system to harness the power of the immune system in
order to treat diseases with unmet medical needs. Cellectis’
headquarters are in Paris, France, with locations in New York, New
York and Raleigh, North Carolina. Cellectis is listed on the Nasdaq
Global Market (ticker: CLLS) and on Euronext Growth (ticker:
ALCLS).
Forward-looking Statements
This press release contains “forward-looking”
statements within the meaning of applicable securities laws,
including the Private Securities Litigation Reform Act of 1995.
Forward-looking statements may be identified by words such as
“anticipate,” “believe,” “intend”, “expect,” “plan,” “scheduled,”
“could” and “will,” or the negative of these and similar
expressions. These forward-looking statements, which are based on
our management’s current expectations and assumptions and on
information currently available to management. Forward-looking
statements include statements about the advancement and the
potential of our innovation and preclinical programs. These
forward-looking statements are made in light of information
currently available to us and are subject to numerous risks and
uncertainties, including with respect to the numerous risks
associated with biopharmaceutical product candidate development.
With respect to our cash runway, our operating plans, including
product development plans, may change as a result of various
factors, including factors currently unknown to us. Furthermore,
many other important factors, including those described in our
Annual Report on Form 20-F and the financial report (including the
management report) for the year ended December 31, 2022 and
subsequent filings Cellectis makes with the Securities Exchange
Commission from time to time, as well as other known and unknown
risks and uncertainties may adversely affect such forward-looking
statements and cause our actual results, performance or
achievements to be materially different from those expressed or
implied by the forward-looking statements. Except as required by
law, we assume no obligation to update these forward-looking
statements publicly, or to update the reasons why actual results
could differ materially from those anticipated in the
forward-looking statements, even if new information becomes
available in the future.
For further information on Cellectis,
please contact:
Media contact:Pascalyne
Wilson, Director, Communications, +33 (0)7 76 99 14
33, media@cellectis.com
Investor Relations
contacts:Arthur Stril, Chief Business Officer, +1 (347)
809 5980, investors@cellectis.comAshley R. Robinson, LifeSci
Advisors, +1 617 430 7577
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