New Immune Data from Ongoing ADXS-NEO Phase 1 Study Support Clinical Potential for Neoantigen-Directed Immunotherapies
July 15 2019 - 8:00AM
Business Wire
- CD8+ T Cell Reactivity Against 90% of Personalized Neoantigen
Targets Confirmed in First of Two Patients
- Proof-of-Mechanism for Off-the-Shelf ADXS-HOT Program with CD8+
T Cells Against Hotspot Mutations
- Antigen Spreading Confirmed
Advaxis, Inc. (NASDAQ: ADXS), a clinical-stage
biotechnology company focused on the discovery, development and
commercialization of immunotherapy products, today announced new
immune data from its ongoing ADXS-NEO Phase 1 clinical trial that
further support the clinical potential for the company’s platform
in neoantigen-directed immunotherapies.
ADXS-NEO is a personalized immunotherapy that is designed to
help a patient’s immune system recognize and respond to
mutation-derived tumor antigens, or neoantigens, that are unique to
his or her tumor. ADXS-NEO is designed to express tLLO fused to up
to 40 patient-specific neoantigens arranged sequentially as
beads-on-a-string. As a live attenuated bacterial vector, ADXS-NEO
can be rapidly taken up by antigen presenting cells, which
recognize it as foreign and present the tLLO-NEO fusion proteins to
T cells by the major histocompatibility complex class I and II
pathways.
ADXS-NEO is being evaluated in an open-label, dose-escalation,
multicenter Phase 1 clinical trial in the United States. Part A of
the study is open to patients with metastatic non-small cell lung
cancer (NSCLC), metastatic microsatellite stable colorectal cancer
(MSS-CRC) and metastatic squamous cell carcinoma of the head and
neck (SCCHN) who will receive ADXS-NEO as monotherapy. Part B of
the study, anticipated to begin later this year, will be open to
NSCLC patients as well as patients with melanoma SCCHN and bladder
cancer and, for this part, ADXS-NEO will be administered in
combination with a checkpoint inhibitor.
The new data were derived from deconvolution of neoantigen pools
using single peptides and in vitro stimulation ELISpot assays
(minimal CD8+ peptides). This has now been completed for the first
two patients enrolled in this study, one with NSCLC and one with
MSS-CRC. Highlights of the new post-vaccination data with ADXS-NEO
are as follows:
- CD8+ T cells were generated against 90% of the 40 neoantigen
targets contained in the drug construct for the MSS-CRC patient
(the NSCLC patient did not have 40 neoantigen targets and there
were certain other issues with this patient’s sample that,
together, made it unsuitable for inclusion in this “hit rate”
analysis). This is consistent with Advaxis’ previously reported
data from its preclinical studies as well as from clinical studies
using pooled neoantigen peptides which were presented at the
American Association of Cancer Research Annual Meeting last year
and earlier this year, respectively. This is the highest “hit rate”
publicly reported to-date in the neoantigen field. This high “hit
rate”, along with the rapid immune responses seen and antigen
spreading, lay the foundation for the ADSX-NEO platform to be
best-in-class for personalized, neoantigen-directed
immunotherapies.
- CD8+ T cells were also generated against the hotspot mutations
found within each of the two patients’ tumors (i.e., EGFRL858R in
the NSCLC patient and KRAS G12A in the MSS-CRC patient). This is
important for the ADXS-NEO program as Advaxis believes a number of
patient tumors likely will present with hotspot mutations, and
generating or maintaining CD8+ T cell activity against these
targets may increase the potential for killing cancer cells. All of
the first four patients in this Phase 1 trial had a hotspot
mutation. This is also relevant for the company’s ADXS-HOT program
in that this is the first time Advaxis has observed the ability to
generate or maintain specific CD8+ T cell activity against hotspot
mutations. Hotspot mutations are important targets contained within
the numerous drug constructs within the ADXS-HOT program and the
specific hotspot mutations in these two patients, EGFRL858R and
KRAS G12A, are included in the company’s ADXS-503 (HOT Lung) and
ADXS-508 (HOT Colorectal) drug constructs, respectively.
- Antigen spreading was confirmed in the MSS-CRC patient showing
specific CD8+ T cells against neoepitopes that were not contained
in the drug construct prepared for this patient (the NSCLC
patient’s sample was not re-tested for antigen spreading). Thus,
Advaxis believes ADXS-NEO may be able to induce a specific immune
response against neoantigen-bearing tumor cells with the resultant
cell death releasing secondary (nontargeted) tumor antigens. These
secondary antigens can then prime subsequent immune responses
(antigen spread) that are thought to be responsible for the
improved clinical outcomes documented with other immunotherapies.
Of note, antigen spreading has also been induced with other Lm
constructs such as ADXS-HPV and ADXS-PSA in cervical and prostate
cancer patients, respectively.
- To date, dosing of ADXS-NEO at 1x108 colony forming units (CFU)
has been well-tolerated in two patients. ADXS-NEO dosed at 1x109
CFU was beyond the maximum tolerated dose with reversible Grade 3
hypoxia (n=2) and Grade 3 hypotension (n=1) dose-limiting
toxicities.
“This preliminary dataset of the deconvolution assays shows the
generation of specific CD8+ T cell response in one MSS-CRC patient
against 90% of the neoantigens in that patient’s personalized Lm
construct together with antigen spreading, both of which we believe
are critical for potential clinical benefit. These encouraging
results are consistent with data from our previous preclinical and
ELISpot-pooled clinical studies, and we look forward to presenting
data from all patients in the monotherapy arm later in the year,”
said Andres Gutierrez, M.D., Ph.D., Chief Medical Officer of
Advaxis. “In addition, we are gaining valuable insight from our
ADXS-NEO platform to help advance our ADSX-HOT drug constructs, as
for the first time we observed the ability to generate specific
CD8+ T cell activity against hotspot mutations in the clinic. We
continue to enroll patients in this Phase 1 study for ADXS-NEO and
look forward to starting Part B with ADXS-NEO in combination with a
checkpoint inhibitor later this year.”
About Advaxis, Inc.
Advaxis, Inc. is a clinical-stage biotechnology company focused
on the discovery, development and commercialization of proprietary
Lm-based antigen delivery products. These immunotherapies are based
on a platform technology that utilizes live attenuated Listeria
monocytogenes (Lm) bioengineered to secrete antigen/adjuvant fusion
proteins. These Lm-based strains are believed to be a significant
advancement in immunotherapy as they integrate multiple functions
into a single immunotherapy and are designed to access and direct
antigen presenting cells to stimulate anti-tumor T cell immunity,
activate the immune system with the equivalent of multiple
adjuvants, and simultaneously reduce tumor protection in the tumor
microenvironment to enable T cells to eliminate tumors. Advaxis has
four programs in various stages of development: ADXS-NEO, a
personalized neoantigen-directed therapy in principle for any solid
tumor; ADXS-503 for non-small cell lung cancer, from its ADXS-HOT
off-the-shelf neoantigen-directed program, ADXS-PSA for prostate
cancer and ADXS-HPV for HPV-associated cancers.
To learn more about Advaxis, visit www.advaxis.com and connect
on Twitter, LinkedIn, Facebook and YouTube.
Advaxis Forward-Looking Statement
Some of the statements included in this press release may be
forward-looking statements that involve a number of risks and
uncertainties. For those statements, we claim the protection of the
safe harbor for forward-looking statements contained in the Private
Securities Litigation Reform Act of 1995. The factors that could
cause our actual results to differ materially include: the impact
of the discontinuation on relationships related to the AIM2CERV
Study; the success and timing of our clinical trials, including
subject accrual; our ability to avoid and quickly resolve any
clinical holds; our ability to obtain and maintain regulatory
approval and/or reimbursement of our product candidates for
marketing; our ability to obtain the appropriate labeling of our
products under any regulatory approval; our plans to develop and
commercialize our products; the successful development and
implementation of our sales and marketing campaigns; the size and
growth of the potential markets for our product candidates and our
ability to serve those markets; our ability to successfully compete
in the potential markets for our product candidates, if
commercialized; regulatory developments in the United States and
other countries; the rate and degree of market acceptance of any of
our product candidates; new products, product candidates or new
uses for existing products or technologies introduced or announced
by our competitors and the timing of these introductions or
announcements; market conditions in the pharmaceutical and
biotechnology sectors; our available cash, including to support
current and planned clinical activities; the accuracy of our
estimates regarding expenses, future revenues, capital requirements
and needs for additional financing; our ability to obtain
additional funding; our ability to obtain and maintain intellectual
property protection for our product candidates; the success and
timing of our preclinical studies including IND-enabling studies;
the timing of our IND submissions; our ability to get FDA approval
for study amendments; the timing of data read-outs; the ability of
our product candidates to successfully perform in clinical trials;
our ability to initiate, enroll, and execute pilots and clinical
trials; our ability to maintain our existing collaborations; our
ability to manufacture and the performance of third-party
manufacturers; the performance of our clinical research
organizations, clinical trial sponsors and clinical trial
investigators; our ability to successfully implement our strategy;
and, other risk factors identified from time to time in our reports
filed with the SEC. Any forward-looking statements set forth in
this press release speak only as of the date of this press release.
We do not intend to update any of these forward-looking statements
to reflect events or circumstances that occur after the date
hereof.
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Investors: LHA Investor Relations Yvonne Briggs, (310) 691-7100
ybriggs@lhai.com
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