ZIOPHARM
Oncology, Inc. ZIOP, a biopharmaceutical company focused on the
development and commercialization of new cancer therapies, and Intrexon
Corporation XON, a leader in synthetic biology, today announced the
presentation of clinical and preclinical studies from their immuno-oncology
programs at the American Association for Cancer Research (AACR) 2014
Immunology and Immunotherapy Meeting taking place December 1-4, 2014 in
Orlando, Florida. Presentations include:
* Clinical results from the Ad-RTS-hIL-12 + veledimex studies in patients
with advanced breast cancer and melanoma demonstrating local and systemic
IL-12-mediated anti-cancer activity, as well as safety through control of
both immune- and IL-12-mediated toxicity with use of the RheoSwitch
Therapeutic System^® (RTS^®) gene switch (Abstract #B11);
* Preclinical data supporting the potential for cytolytic activity against
solid tumor targets with allogeneic, genetically-modified stem cells
enabled for controlled release of cell-linking moieties (CLMs) within the
tumor micro-environment (Abstract #B25); and
* Preclinical data describing the development of a novel, high-throughput
screening technology for rapidly identifying bi-specific antibodies
capable of inducing targeted immunologic activity through the activation
of T-cells or other immune cells against tumors (Abstract #B16).
"The goal of immuno-oncology is to produce powerful immune responses to
cancer. Controlling these immune responses and being able to keep patients out
of the ICU during treatment would be an important advance," said James
Armitage, M.D., Professor, Department of Internal Medicine, Joe Shapiro
Distinguished Chair of Oncology, University of Nebraska Medical Center,
ZIOPHARM Medical Board member, and Past President of ASCO and the American
Society for Blood and Marrow Transplantation. "A key to achieving this is to
tightly control immune system effectors, activating and modulating the
intensity of the response as necessary. These data demonstrate the ability to
do just that, showing novel control over effector expression, not only in the
lab, but also in the clinic."
Interim clinical trial results continue to validate dose-dependent oral
veledimex control of the Interleukin-12 (IL-12) gene program module and the
rapid reversibility of cytokine expression and associated adverse events in
patients upon withdrawal of the activator ligand. Together the Companies
intend to integrate this RTS-hIL-12 veledimex-controlled cytokine module into
a suite of next generation cellular products armed with tumor specific
targeting and signaling through chimeric antigen receptor (CAR), T-Cell
Receptor (TCR), and cell linking moiety (CLM) platforms.
"Through the rational design of molecularly directed T-cell therapies, such as
CAR-T and CLM, and controlled expression of cytokine adjuvants with our
clinically validated RTS^® platform, we plan to advance cellular therapies
that overcome the challenges of treating solid tumor malignancies and improve
upon the limitations of current hematologic approaches within
immuno-oncology," stated Gregory Frost, Ph.D., Senior Vice President and Head
of Intrexon's Health Sector.
Results in detail
"Ad-RTS-hIL-12 + Veledimex Regulation of IL-12 Expression in Advanced Breast
Cancer (BC) and Melanoma Patients" (Abstract #B11)
In two open-label Phase II clinical studies, twelve patients with metastatic
advanced stage breast cancer and twenty-six patients with metastatic melanoma
were administered Ad-RTS-hIL-12, a novel DNA-based therapeutic candidate for
the controlled expression of IL-12, a potent cytokine for stimulating an
anti-cancer T-cell immune response. Following intra-tumoral injection of
Ad‑RTS‑hIL‑12, expression of IL-12 within patients was controlled by the
RheoSwitch Therapeutic System^® (RTS^®) gene switch using the oral activator
ligand, veledimex, at doses ranging from 5mg to 160mg. All subjects had heavy
tumor burden and disease progression at the time of enrollment, with mean
number of prior therapies at 14 and 10 for breast cancer and melanoma
patients, respectively. Treatment with Ad-RTS-hIL-12 + veledimex resulted in
an increase in the immune cytokine IL-12 and downstream cytokines, IFNg, IP-10
and IL-10, resulting in a significant increase in the number of CD8+ T-cells.
Among seven evaluable subjects in the Phase II clinical study of Ad-RTS-IL-12
+ veledimex in patients with recurrent or metastatic breast cancer, three had
stable disease, including one triple negative BC subject who crossed the
primary endpoint of 16 week progression free survival, for a disease control
rate (stable disease or better) of 43%. Target lesions and tumor burden were
significantly reduced in approximately 40% of patients. In the Phase I/II
study of Ad-RTS-hIL-12 + veledimex in subjects with unresectable stage III/IV
melanoma, of eighteen evaluable subjects, one had a partial response and six
had stable disease, for a disease control rate of 39%. In melanoma patients
for whom a response was observed, there was evidence of local and systemic
anti-cancer activity.
The adverse event profile of Ad-RTS-hIL-12 + veledimex in both melanoma and
breast cancer was predictable, reversible and characteristic of immune
activation. The most common ≥ Grade 3 treatment emergent adverse events
(TEAEs) in breast cancer and melanoma included neutropenia and electrolyte
abnormalities (21%) each, LFTs increased (16%), leukopenia (13%) and pyrexia,
hypotension, lymphopenia, anemia, and cytokine release syndrome (11%) each.
Importantly, all TEAEs and SAEs ≥ Grade 3 reversed rapidly upon
discontinuation of veledimex oral dosing.
Based on these results, ZIOPHARM expects to initiate a Phase 1b/2 clinical
trial of Ad-RTS-hIL-12 + veledimex in conjunction with standard-of-care
treatment in subjects with earlier-stage, locally advanced or metastatic
breast cancer. The Company also continues to work with regulators toward the
initiation of a Phase I trial of Ad-RTS-IL-12 as a single agent in the
treatment of patients with Glioblastoma Multiforme, anticipated to begin in
the first half of 2015, and is exploring additional applications using the
RTS^® control system for IL-12 cell-based therapies.
"With potent, systemic anti-cancer immune activity and control of both immune-
and IL-12-mediated toxicity established in heavily pretreated breast cancer
and melanoma patients, our development strategy for this novel therapy is in
sharp focus," said Francois Lebel, M.D., Senior Vice President, Clinical
Development and Medical Operations at ZIOPHARM. "These findings will be
translated into a study of patients with early metastatic breast cancer
responding to standard therapy, where an increase in tumor specific CD8+
T-cells may improve clinical outcomes. As we evolve this platform, we look
forward to exploring its further clinical application in cancers where an
IL-12 driven immune response is associated with anti-cancer immunity and where
combination therapy may deliver significantly improved outcomes for patients."
"Development of a High-Throughput Imaging Screen for the Functional Assessment
of Cell-Linking Moieties Using Effector And Target Cells In A Cell Kill Assay"
(Abstract #B16) and "Controlled Production of a Bispecific Antibody by a
Genetically-modified Stem Cell Triggers T-cell Activation and Cytolysis in
Non-small Cell Lung Carcinoma" (Abstract #B25)
Cell Linking Moieties (CLMs) are small bi-specific antibody fragments capable
of directing potent T-cell mediated tumor lysis by bridging the immunologic
synapses of T-cells and surface targets on tumor cells. Previous studies have
shown that the systemic distribution and pharmacokinetic profile of
bi-specific antibodies limit their utility for many target/effector
combinations. In two preclinical studies, Intrexon and ZIOPHARM researchers
interrogated a large number of CLM-based effectors for their ability to
activate white blood cells from peripheral blood and lyse receptor
target-positive tumor cells. Allogeneic, tumor targeting stem cells were then
genetically modified to express CLMs within the tumor microenvironment using
the RheoSwitch Therapeutic System^® platform as a mechanism for providing
spatial and temporal control.
The first study demonstrates the ability of Intrexon's proprietary image-based
screening systems and rapid DNA assembly to screen a large number of EGFR and
HER2 receptor-targeted CLM variants for their ability to recruit CD3+ T-cells
and mediate selective cell killing against target positive cells in peripheral
blood co-cultures. The image-based screening platform allows for real time
target cell killing information to be obtained, as well as kinetic cell
morphologic analyses to understand the dynamics of killing activity, thereby
shortening the developmental timeline to lead candidate selection.
The second study validated these CLM candidates in scalable, allogeneic
endometrial regenerative cells (ERCs) genetically modified to express an
anti-CD3-anti-EGFR CLM under RTS^® ligand inducible control. Expression of
CLMs under the RTS^® inducible promoter provided effective control of CLM
secretion and modulation of killing activity, with veledimex-dependent
cytotoxicity of greater than 80% against an EGFR+ KRAS mutant lung cancer cell
model. CLM-expressing ERCs were found to be effective in co-culture killing
assays at cellular doses as low as 1% of target cells.
These data support the feasibility of localized cytolytic activity of
CLM-secreting allogeneic cell therapy products against EGFR+ KRAS mutant solid
tumor malignancies.
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