Lyell Immunopharma, Inc. (Nasdaq: LYEL), a clinical‑stage T-cell
reprogramming company advancing a diverse pipeline of cell
therapies for patients with solid tumors, today announced initial
clinical and translational data from its Phase 1 trial of LYL797,
its first-generation reprogrammed ROR1 CAR T‑cell product candidate
enhanced with proprietary anti-exhaustion technology. The initial
dataset consists primarily of patients with triple-negative breast
cancer (TNBC) and demonstrated dose-dependent antitumor clinical
activity and the ability of LYL797 CAR T cells to proliferate,
infiltrate tumors and kill cancer cells in patients with
relapsed/refractory disease. Patients with TNBC treated with LYL797
had an objective response rate (ORR) of 40% and clinical benefit
rate (CBR) of 60% at the 150 x 106 CAR T cell dose level, with a
CBR of 38% across all dose levels evaluable to date. Common
treatment-related adverse events in patients without lung
metastases included Grade 1 and 2 cytokine release syndrome (CRS)
and headache, and the expected cytopenia from lymphodepletion.
There were no reports of immune effector cell-associated
neurotoxicity syndrome (ICANS) attributed to LYL797. Pneumonitis
occurred in patients with lung metastases and dose escalation is
continuing separately and more gradually in those patients. No
dose-limiting toxicities have been reported in patients without
lung involvement. All patients are now receiving prophylactic
steroids prior to LYL797 treatment.
“These are promising initial clinical findings demonstrating
that LYL797 ROR-1-targeted CAR T cells had dose-dependent antitumor
clinical activity and have the potential to deliver even more
meaningful and durable benefit to patients as we continue to dose
escalate,” said David R. Spigel, MD, Chief Scientific Officer at
the Sarah Cannon Research Institute, medical oncologist and a lead
investigator in the LYL797 study. “Pneumonitis is a known
complication of radiotherapy and several approved cancer therapies,
including immune checkpoint blockade and several antibody-drug
conjugate therapies. We have implemented a protocol using steroids,
the standard of care for treatment of patients with pneumonitis,
that I believe will enable us to successfully monitor and manage
these events.”
The LYL797 study includes a robust translational program from
which Lyell reports the first demonstration that CAR T cells
enhanced with anti-exhaustion technology expanded, persisted and
infiltrated into solid tumors, in some cases with associated
evidence of cancer cell killing. TIGIT, a marker of T cell
exhaustion, was measured in samples collected on Day 11
post-infusion with only a low proportion of LYL797 CAR T cells
demonstrated to be TIGIT-positive. RNAseq data also suggested a
significant proportion maintained the targeted stem-like and
effector memory cell phenotype.
“We are encouraged to see clinical responses and a clear
dose-dependent indication of antitumor clinical activity from
treatment with LYL797 in patients with advanced triple-negative
breast cancer,” said Lynn Seely, MD, President and Chief
Executive Officer of Lyell. “Our translational data provide, to our
knowledge, the first demonstration of persistent CAR T cell
infiltration into solid tumors associated with evidence of cancer
cell killing. This early validation of our anti-exhaustion
technology gives us the conviction to expand our trial to include
patients with ROR1+ ovarian or endometrial cancers, while
continuing to enroll patients with triple-negative breast or
non-small lung cancers, and also to initiate a new clinical trial
for patients with multiple myeloma and chronic lymphocytic
leukemia. This compelling early clinical data from LYL797 gives us
a high degree of confidence to advance LYL119, our next generation
ROR1-targeted product candidate with even more powerful
anti-exhaustion technology. We have submitted an IND for LYL119 and
expect to enter the clinic this year.”
Initial LYL797 Phase 1 Clinical Trial
Results
This initial dataset of 20 treated patients includes 16 patients
with TNBC and four patients with non-small cell lung cancer. All
patients enrolled had relapsed/refractory metastatic disease and
the mean lines of prior therapies for metastatic disease was six.
Four dose levels, including two interim dose levels, have been
explored to date: 50 x 106 cells, 100 x 106 cells, 150 x 106 cells
and 300 x 106 cells. The efficacy evaluable subset includes 16
patients, and the safety evaluable subset includes 18 patients. The
manufacturing success rate was 100%.
Of the five patients with TNBC treated with LYL797 at the 150 x
106 cell dose level, the highest dose level cleared to date, two
patients had confirmed partial responses to Day 90, resulting in an
ORR of 40%. The CBR, defined as a best response of stable disease,
partial response or complete response, was dose-dependent with 60%
at the 150 x 106 cell dose level and 38% across all four dose
levels evaluated.
The most frequently reported related adverse events of any grade
are CRS (61%), pneumonitis (22%) and headache (17%), as well as the
expected cytopenia from lymphodepletion in all patients. The CRS
was generally mild (Grade 1 or 2 only), characterized by fever, and
treated with tocilizumab and steroids. There were no reports of
immune effector cell-associated neurotoxicity syndrome (ICANS)
attributed to LYL797. The most frequently reported Grade
> 3 related adverse events were pneumonitis (17%) and
hypoxia (11%), as well as the expected cytopenia from
lymphodepletion in 78% of patients. One patient had Grade 5
respiratory failure on Day 41. The adverse event of Grade
> 3 pneumonitis occurred only in patients with TNBC and
lung metastases, resulting in the separation of dose escalation
into two cohorts based upon lung involvement (lung primary, lung
metastatic disease or pleural effusion). No dose-limiting
toxicities occurred in patients without lung involvement. All
patients are now receiving prophylactic therapy with dexamethasone
to mitigate pneumonitis. Patients without lung involvement are
currently under evaluation at the 300 x 106 cell dose level and
patients with lung involvement are currently under evaluation at 75
x 106 cell dose level.
Translational data are described on a subset of patients and
include CAR T cell expansion in peripheral blood, phenotypic
analysis of T cell exhaustion and stem-like markers and on-study
tumor biopsies to assess for CAR T cell tumor infiltration. LYL797
CAR T-cell expansion was observed in peripheral blood samples at
Day 60 in all patients assessed to date (n = 11) with peak
expansion occurring between Days 8 and 11. Peak expansion was on
average three-fold higher in patients receiving 150 x 106 cells
compared to those receiving 50 x 106 cells. The exhaustion marker,
TIGIT, was found only in a low proportion of LYL797 CAR T cells at
Day 11 (n = 4) providing support for the role of c-Jun
overexpression as an anti-exhaustion technology. A significant
proportion of cells with stem-like and effector memory phenotypes
were demonstrated at Days 11 and 22 following RNAseq transcriptomic
analysis supporting the role of Epi-R to preserve a stem-like
phenotype. Nine evaluable on-treatment tumor biopsies collected
between Days 21 and 30 after LYL797 infusion were assessed. LYL797
CAR T cells were present in all solid-tumor biopsies, indicating
that LYL797 CAR T cells enhanced with Lyell’s anti-exhaustion
technology were able to infiltrate and persist in the solid tumor
microenvironment. In addition, the tumor biopsies have features
consistent with T cell-mediated tumor lysis, including T cell-rich
inflammation with scattered tumor cells.
Conference Call and Webcast Details
Lyell’s management, together with David R. Spigel, MD, Chief
Scientific Officer at the Sarah Cannon Research Institute and a
lead investigator in the Phase 1 clinical trial, will host an
investor conference call and Webcast beginning at 8:30 am ET today,
to discuss the initial data from the LYL797 Phase 1 clinical
trial.
- The Webcast can be accessed here.
- To join the live conference call, please register here to
receive a dial-in number and unique PIN to access the call.
It is recommended callers join ten minutes prior to the start of
the event (although you may register and join at any time during
the Webcast). A replay of the event and presentation materials will
be archived on the Investor page of the Lyell Website following the
end of the event.
LYL797 Phase 1 Clinical Trial Design
(NCT05274451)
The Phase 1 clinical trial is designed as an open-label,
dose-escalation and expansion trial in patients with
relapsed/refractory TNBC who have failed at least two lines of
therapy and NSCLC who have failed at least one line of therapy. The
trial has been amended to also include patients with
platinum-resistant ovarian cancer or endometrial cancer. All
patients enrolled have tumor specimens positive for ROR1 protein
expression by immunohistochemistry.
More information on the Phase 1 trial can be found on
clinicaltrials.gov here.
About LYL797
LYL797 is a receptor tyrosine kinase-like orphan receptor 1
(ROR1) -targeted CAR T‑cell product candidate enhanced with Lyell’s
anti-exhaustion genetic reprogramming technology (c-Jun) and
epigenetic reprogramming technology (Epi-R). LYL797 overexpresses
c-Jun to correct for an imbalance in the AP-1 family of
transcription factors present in exhausted T cells. In preclinical
studies, overexpression of c-Jun enables T cells to resist
exhaustion, infiltrate solid tumors and maintain their
functionality. LYL797 is manufactured utilizing Epi‑R, Lyell’s
proprietary ex vivo manufacturing protocol that is designed to
generate populations of stem-like T cells with reduced exhaustion
and improved proliferation and antitumor activity.
ROR1 is a fetal protein expressed during embryogenesis and is
believed to be important in cell migration, polarity and survival.
Significant subsets of patients with common cancers express ROR1
and it is generally associated with a poor prognosis.
About Lyell Immunopharma, Inc.
Lyell is a clinical-stage T-cell reprogramming company advancing
a diverse pipeline of cell therapies for patients with solid
tumors. Lyell is currently enrolling a Phase 1 clinical trial
evaluating a first-generation ROR1-targeted CAR T-cell therapy
enhanced with anti-exhaustion technology in patients with
relapsed/refractory triple-negative breast cancer, non-small cell
lung cancer (NSCLC), ovarian cancer and endometrial cancer. A
second Phase 1 clinical trial is ongoing to evaluate reprogrammed
tumor infiltrating lymphocytes (TIL) in patients with advanced
melanoma, NSCLC and colorectal cancer. An investigational new drug
application has been submitted to the FDA for LYL119, a
next-generation ROR1-targeted CAR T-cell product candidate with
even more powerful anti-exhaustion technologies.
The technologies powering Lyell’s product candidates are
designed to address barriers that limit consistent and long-lasting
responses to cell therapy for solid tumors: T-cell exhaustion and
lack of durable stemness, which includes the ability to persist and
self-renew to drive durable tumor cytotoxicity. Lyell is applying
its proprietary ex vivo genetic and epigenetic reprogramming
technologies to address these barriers to develop new medicines
with improved durable clinical outcomes. Lyell is based in South
San Francisco, California with facilities in Seattle and Bothell,
Washington. To learn more, please visit www.lyell.com.
Forward Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995. Forward-looking statements expressed or implied in this press
release include, but are not limited to, statements regarding: the
continued clinical progress of the LYL797 trials; the effectiveness
of prophylactic steroids or other treatments to mitigate adverse
events; the potential to deliver more meaningful and durable
benefit to patients with dose escalation; Lyell’s plans to enroll
patients with platinum-resistant ovarian cancer and endometrial
cancer in the LYL797 trial; Lyell’s plans to submit an IND for
LYL797 to initiate a new Phase 1 study evaluating LYL797 in
patients with multiple myeloma or chronic lymphocytic leukemia and
the timing thereof; Lyell’s development plans for LYL119 and the
effectiveness of any technologies incorporated into LYL119; the
ability of Lyell’s reprogramming technologies to infiltrate and
persist in the solid tumor microenvironment; and other statements
that are not historical fact. These statements are based on Lyell’s
current plans, objectives, estimates, expectations and intentions,
are not guarantees of future performance and inherently involve
significant risks and uncertainties. Actual results and the timing
of events could differ materially from those anticipated in such
forward-looking statements as a result of these risks and
uncertainties, which include, but are not limited to, risks and
uncertainties related to: macroeconomic conditions, including the
effects of geopolitical instability and actual or perceived changes
in interest rates and economic inflation; Lyell’s ability to submit
planned INDs, obtain approval of submitted INDs, or initiate or
progress clinical trials on the anticipated timelines, if at all;
the potential for results from clinical trials to differ from
nonclinical, early clinical, preliminary or expected results;
Lyell’s limited experience as a company in enrolling and conducting
clinical trials, and lack of experience in completing clinical
trials; Lyell’s ability to manufacture and supply its product
candidates for its clinical trials; the nonclinical profiles of
Lyell’s product candidates or technology not translating in
clinical trials; significant adverse events, toxicities or other
undesirable side effects associated with Lyell’s product
candidates; the significant uncertainty associated with Lyell’s
product candidates ever receiving any regulatory approvals; Lyell’s
ability to obtain, maintain or protect intellectual property rights
related to its product candidates; implementation of Lyell’s
strategic plans for its business and product candidates; the
sufficiency of Lyell’s capital resources and need for additional
capital to achieve its goals; and other risks, including those
described under the heading “Risk Factors” in Lyell’s Annual Report
on Form 10-K for the year ended December 31, 2023, filed with the
Securities and Exchange Commission (SEC) on February 28, 2024, and
the Quarterly Report on Form 10-Q for the quarter ended March 31,
2024, filed with the SEC on May 6, 2024. Forward-looking statements
contained in this press release are made as of this date, and Lyell
undertakes no duty to update such information except as required
under applicable law.
Contact:Ellen RoseSenior Vice President,
Communications and Investor Relationserose@lyell.com
Lyell Immunopharma (NASDAQ:LYEL)
Gráfica de Acción Histórica
De May 2024 a Jun 2024
Lyell Immunopharma (NASDAQ:LYEL)
Gráfica de Acción Histórica
De Jun 2023 a Jun 2024