Preparation of osteosarcoma cells. Osteosar-
coma cells were obtained from primary tumors. The
tumor tissues were separated in Hank’s balanced
salt solution (Ca++/Mg++ free) containing 1 mg/ml col-
lagenase, 0.1 mg/ml hyaluronidase and then cultured
in RPMI 1640 medium supplemented with 10% heat-
inactivated autologous human serum, L-glutamine
(2 mM), penicillin (100 U/ml) and streptomycin
(100 µg/ml) until they were fused with DCs.
Fusion of DCs with osteosarcoma cells. Au-
tologous DCs were incubated with osteosarcoma
cells at a ratio of 5 : 1 and suspended in 0.3 M glucose
solution containing 0.1 mM Ca(CH3COO)2, 0.5 mM
Mg(CH3COO)2, and 0.3% bovine serum albumin. The
pH of the fusion medium was adjusted to 7.2–7.4 with
L-histidine (all chemicals were from Sigma, USA). After
centrifugation, the cells were resuspended in the same
fusion medium without bovine serum albumin. Routinely,
0.5 ml of cell suspension containing 6 x 106 cells were
processed using a specially designed electroporation
cuvette, precoated on one side with paraffin wax (50 µl
per cuvette). For electrofusion, a pulse generator (model
ECM 2001, BTX Instrument, Genetronics, San Diego,
CA) was used. Electrofusion involves two independent
but consecutive steps. The first reaction is to bring cells
in close contact by dielectrophoresis, which can be
accomplished by exposing cells to an alternating (ac)
electric field of relatively low strength. Then cell fusion
can be triggered by applying a single square wave pulse
to induce reversible cell membrane breakdown in the
zone of membrane contact. For the current study, the
optimal conditions for maximum electrofusion efficiency
without substantial cell death (not lower than 70% vi-
ability by Trypan Blue staining) were found to consist
of two consecutive rounds of an alignment pulse of 50
V for 5 s followed by a fusion pulse of 250 V. The entire
process was repeated a second time to maximize fusion
efficiency. The fusion mixture was allowed to stand for
5 min before suspending in complete medium and then
incubated at 37 °C overnight. The nonadherent cells con-
sisted of mainly DCs, and the adherent cells consisted
of mainly fusion cells and tumor cells. The electrofusion
products were purified by monoclonal antibody CD1α (a
DC marker not expressed on tumor cells) sticking to the
magnetic beads (Miltenyi Biotec, German).
Transmission electron microscopy.For observa-
tion of cell morphology and intracellular structure, cell
preparation was fixed with 1.5% glutaraldehyde in 0.1 M
cacodylate buffer, pH 7.4, for 1 h at 4 °C. The specimens
were washed, treated with 1% osmium tetroxide in 0.1 M
cacodylate buffer, and passed through an alcohol gradi-
ent. They were treated with propylene oxide and embed-
ded. The ultrathin sections were cut with an MT2 Sorvall
ultramicrotome and examined with a JEOL-100-CX
transmission electron microscope (TEM).
Flow cytometry. The patient derived osteosar-
coma cells, DCs and purified fusion cells were washed
and incubated with monoclonal antibodies against
HLA-ABC, HLA-DR, CD14, CD40, CD1α, CD83, CD86,
and MUC1 (all prime antibodies from Serotec Systems,
UK) for 1 h on ice. After washing with PBS, the cells
were incubated with fluorescein isothiocyanate (FITC)/
phycoerythrin(PE)-conjugated goat anti-mouse IgG
(PharMingen, USA) for 30 min. Samples were then
washed, fixed with 2% paraformaldehyde, and ana-
lyzed by FACScan (Becton Dickinson, USA).
Autologous T cell proliferation assay.Autologous
PBMC from the same osteosarcoma patient from whom
fusion cells were derived were purified through nylon wool
to remove APCs and B cells. The T cells were cocultured
with autologous DC/osteosarcoma fusion cells, DCs
mixed osteosarcoma cells and osteosarcoma cells alone
for 5 days in complete RPMI 1640 medium supplemented
with 10% human serum, 20 U/ml human IL-2, 50 µM
2-mercaptoethanol, 2 mM L-glutamine, 10 μM Hepes,
100 U/ml penicillin and 100 μg/ml streptomycin. Then the
cells were pulsed with 1 µCi 3H-Thymidine (New England
Nulear, Boston, MA) per well for 12 h, and T cell prolif-
eration was measures using standard [3H]-thymidine
incorparation. All samples were conducted in triplicate
and expressed as mean ± S.D.
Measurement of CTL activity.
PBMC from osteosarcoma patients were stimulated by co-culturing
with autologous DC/osteosarcoma fusion cells in the
presence of 20 U/ml human IL-2. PBMC cocultured
with DCs mixed with tumor cells, DCs, or tumor cells
alone were used as a control. The stimulated T cells
were harvested at the indicated time, separated by
passing through nylon wool and used as effector
cells in the CTL assay. Autologous osteosarcoma
cells, monocytes, MG63 osteosarcoma cells, LNCap
prostate cancer cells, and K562 cells were labeled
with 51Cr for 60 min at 37 °C. After washing, target cells
(2 x 104) were cocultured with T cells for 5 h at the
indicated cell radio. Supernatants were assayed in a
gamma counter for 51Cr release. Spontaneous release
of 51Cr was assessed by incubation of the targets in the
absence of effectors. Maximum or total release of 51Cr
was determined by incubation of the targets in 0.1%
Triton X-100. The percentage of specific 51Cr release
was determined by the following calculation:
percentage-specific release = [(experimental –
spontaneous)/(maximum - spontaneous)] x 100.
Statistical analysis. Statistical significance was
determined using Student’s t-test.
Results
Morphology and phenotype of DCs, osteosar-
coma and fusion cells.After culturing and induction,
DCs displayed typical morphology with elongated den-
dritic processes (Fig. 1, left panel), whereas osteosar-
coma cells had a thick cell coat and round shape (see
Fig. 1, middle panel). The fusion of osteosarcoma cells
with DCs resulted in a larger hybrid cell with both DCs
and tumor cells (see Fig. 1, right panel) and irregular
surface, suggesting the integration of two or more
cells. Phenotypically, HLA-ABC, HLA-DR, CD14, CD40,
CD1α, CD83, CD86, and MUC1 were detected on the
three populations (Fig. 2). Human DCs expressed
CD1α, but not MUC1 antigens, osteosarcoma cells
expressed tumor-associated MUC1 antigens but not
CD1α, and the purified DC/osteosarcoma fusion cells
highly expressed both CD1α and MUC1 (Fig. 3).
fig. 2. DCs (solid bar), osteosarcoma cells (hatched bar) and
purified DC/osteosarcoma fusion cells (gray bar) from the patient
with osteosarcoma were stained with panels of mAbs and analyzed
by flow cytometry for the expression of the indicated molecules
Stimulation of autologous T cell proliferation by
DC/osteosarcoma fusion cells. To determine the ef-
fects of DCs mixed with osteosarcoma cells or DC/oste-
sarcoma fusion cells in stimulation of T cells, autologous
T cells were cocultured with the mixture or the fusion hy-
brids and their proliferation was measured. As a control,
the T cells were also cocultured with autologous tumor
cells. The results demonstrated little if any evidence for T
cell stimulation by autologous tumor cells, tumor cells, or
the mixture of the two cell types. By contrast, incubation
of T cells with autologous fusion cells was associated with
T cell proliferation (Fig. 4). This finding demonstrates that
fusion of osteosarcoma cells and DCs results in stimula-
tion of a specific T cell response.
fig. 4. Stimulation of T cell by DC/osteosarcoma fusion cells. T
cell were cultured with osteosarcoma cells, osteosarcoma cells
mixed with DCs, or DC/osteosarcoma fusion cells at indicated
ratios of T cells to stimulators
CTL activity against autologous tumors induced
by DC/osteosarcoma fusion cells. To assess the in-
fig. 1. Surface and intracellular structure of cells examined by transmission electron microscopy (× 4000). DCs displayed typical
morphology (left panel); osteosarcoma cells had a thick cell coating and round shape (middle panel); the fusion construct of
osteosarcoma cells with DCs resulted in a larger hybrid cell with both DCs and tumor cells (right panel)
fig. 3. FACS analysis of DCs, osteosarcoma cells and DC/osteosarcoma fusion cells. DCs (left panel), osteosarcoma cells (middle
panel), and DC/osteosarcoma fusion cells (right panel) were stained with anti-MUC1, and anti-CD1α mAbs and analyzed by two-
color flow cytometry
duction of tumor-specific CTLs, T cells were stimulated
for 10 days and then isolated for assaying lysis of au-
tologous tumor cells. T cells incubated with autologous
DCs, osteosarcoma cells, or an unfused mixture of both
exhibited a low level of autologous osteosarcoma cell
lysis (Fig. 5). Also, T cells stimulated with the fusion cells
were effective in inducing cytotoxicity of autologous tu-
mor. These results are consistent with our previous find-
ing that fusion between DCs and tumor cells is critical
for the hybrid cells to acquire the stimulating ability.
fig. 5. Activation of anti-tumor CTLs by autologous fusion cells.
T cell were stimulated with autologous DCs, autologous osteosar-
coma cells, osteosarcoma cells mixed with DCs, or DC/ osteosa-
rcoma fusion cells at indicated ratios of T cells to stimulators
Osteosarcoma-specific CTLs induced by DC/os-
teosarcoma fusion cells. To determine the specificity
of the CTLs induced by fusion cells, multiple targets were
used in a parallel assay. T cells stimulated by DC/osteosa-
rcoma fusion cells lysed aotologous osteosarcoma cells,
but not autologous monocytes, MG63 osteosarcoma
cells, LNCap prostate cancer cells and natural killer-sensi-
tive K562 cells. In addition, the CTL activity was inhibited by
anti-HLA class I antibody, indicating HLA class I-restricted
mechanism. Collectively, these results indicate that the
CTLs induced by DC/osteosarcoma fusion cells are os-
teosarcoma-specific and MHC class I-restricted
fig. 6.Specificity of CTLs generated by autologous fusion cells.
T cell were stimulated with DC/osteosarcoma fusion cells were
incubated with 51Cr-labeled autologous osteosarcoma cells (OS),
autologous monocytes (MC), MG63 cells, LNCaP prostate can-
cer cells, or K562 cells at a ratio 40 : 1 (solid bars). The targets
were also preincubated with an anti-HLA class I antibody (W6/32;
dilution 1 : 100) and then assayed for lysis (hatched bars). CTL
activity was determined by 51Cr release. The results are expressed
as mean ± SD of three replicates
discussion
Osteosarcomas are the prominent primary bone
cancers in humans, excluding hemopoietic malignan-
cies. They mainly affect children and adolescents and
are usually highly aggressive and eventually lethal. In an
attempt to individualize the therapeutic interventions of-
fered to osteosarcoma patients, immunotherapy might
make a contribution to the prevention and cure [18].
In immunotherapy, DC-based vaccine affords a
promising new approach for the clinical response of
cancers and has become an issue of the highest inter-
est. Fused DC-tumor cells present to CD4+ T-helper
cells a high level T cell costimulatory and MHC mol-
ecules, both of which are absent in most tumor cells.
This engagement results in the up-regulation of cell
surface markers on T-helper cells and the secre-
tion of various cytokines. The CD4+ T cell therefore
provides “help” by generating potent CTLs that are
the principal effectors of specific antitumor immune
responses [19–20]. Our current work aimed to explore
an alternative approach to a DC-based vaccine for
osteosarcoma and demonstrate that the electrofusion
cells are functional in inducing osteosarcoma-specific
and MHC class I-restricted CTL activity.
In this study, an electrofusion protocol was em-
ployed and a standard CTLs assay was adopted. Sig-
nificantly, one important advantage of immunization
with electrofusion products is the potential to induce an
immune response against all possible tumor antigens,
known or unknown. Several in vitroand in vivoapplica-
tions have been explored for the use of electrofused
DC-tumor hybrids as APCs [21–23]. From the results
obtained in the present studies, we could conclude that
the fusion cells were effective in inducing anti-tumor
CTLs, which lyse autologous osteosarcoma cells by an
MHC class I-restricted mechanism. Characterization of
the peptides recognized by these CTLs can be used to
identify tumor-associated antigens that are the targets
of the immune response.
Recently, there have been many relevant outcomes
about using allogenic DCs as fusion partners [24–25], for
T cells are potentially activated through both MHC class
I molecules derived from tumor cell and co-stimulatory
and adhesion molecules from allogenic DCs. Allogenic
DCs express many co-stimulatory and adhesion mol-
ecules that provide secondary signals for stimulation of
active T cell populations in the same way and secrete
a variety of cytokines additionally [26–28]. This option
seemed to project a practical advantage, for in a clinical
setting, allogenic DCs can be generated conveniently
from stored peripheral mononuclear cells from normal
healthy volunteers from the general population. How-
ever, there have been little proofs so far that autologous
DC/osteosarcoma fusion cells as tumor vaccine could
be effective in stimulating T cells, so we are determined
to explore the biology and efficacy of electrofusion cell
immunization against osteosarcoma gradually and more
studies on allogenic fusion cells will be investigated.
Unfortunately, the characterization and selection of
DC/osteosarcoma fusion cells remain a challenge due
to the lack of an unique marker for the osteosarcoma
cells. In the present study, we selected a representa-
tive marker based on the phenotype of tumor cells
in the patient. MUC1 was used as a tumor marker in
osteosarcoma patients since peripheral blood derived
DCs expressed minimal MUC1.
In summary, this study has demonstrated that it’s
feasible to generate a large number of DC/osteosa-
rcoma hybrid cells by the electrofusion technique.
Compared with other methods, electrofusion could
be reproducible and the fusion rate tended to be high.
Autologous DCs fused with osteosarcoma cells were
capable of inducing a potent antitumor response and
could be employed to treat the malignant bone tumor
effectively. This approach could conceivably be ap-
plied to a wide range of cancer indications for which
tumor-associated antigens have not been identified.
Acknowledgments
This work is sponsored by the National Natural
Science Foundation (30330610, CHN). We would like
to thank Professor Zhang Dianzhong for his technical
help and Zhang Yunfei for his efforts in interpreting
and analyzing the data. We also thank Dr. Long Hua
for his valuable advice.
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A New Type of Dendritic Cell-Based Cancer Vaccine has Received Approval for Clinical Tests and at the Same Time Secures Substantial Financing
Category dendritic, Immune System, Kidney, Vaccine
press release
Nov. 25, 2011, 6:57 a.m. EST
GOTHENBURG, Sweden, November 25, 2011 /PRNewswire via COMTEX/ — Immunicum, which is developing cancer vaccines, has received approval from the Swedish Medical Products Agency to start its first clinical trial. The study will be conducted on kidney cancer patients at the University Hospital in Uppsala. At the same time, the company secures substantial financing to complete the clinical trial.
It’s a big and important step to test the vaccine on humans for the first time. Our animal studies have shown good results, so we feel safe to continue, says Jamal El-Mosleh, CEO of Immunicum.
Immunicum’s patented cancer vaccine is based on over 20 years of research in the field of transplantation immunology and activates the body’s own immune system to attack tumor cells. The Nobel Prize in Medicine was recently awarded the discoverer of dendritic cells and their role in immunological reactions, the same type of cells that Immunicum bases its vaccines on.
However, our vaccines differ from other cancer vaccines. Traditionally, dendritic cell-based cancer vaccines are made from patients’ own cells. This means that each vaccine must be specially made for each patient, which is expensive, complex and takes time. Moreover, it is physically stressful for the patient who is seriously ill, says Jamal El-Mosleh.
Immunicum’s vaccine is based on using dendritic cells from healthy individuals and can thus be mass-produced, leading to significant commercial advantages.
The vaccine has been tested in animal studies to examine its therapeutic effect and tumors were reduced in both weight and volume. Toxicity studies have also been conducted to investigate possible side effects, especially with a focus on autoimmune diseases. The study showed no evidence of adverse side effects.
Through the green light from the Medical Products Agency, a clinical phase I/II trial will be initiated within the next few months on twelve patients with metastatic renal cancer. To finance the trial, Immunicum secures the largest capital injection in the company’s history through a successful new share issue.
The study will last for about a year and we will evaluate both safety and efficacy of the vaccine, says Jamal El-Mosleh.
More on Immunicum
Immunicum develops therapeutic cancer vaccines. The patented technology is based on over 20 years of research in the field of transplantation immunology and activates the body’s own immune system to attack harmful substances such as tumor cells. Unlike competing dendritic cell-based cancer vaccines, Immunicum’s vaccines are able to mass produce.
http://www.immunicum.com
For further information contact: Jamal El-Mosleh, CEO of Immunicum, jamal.el-mosleh@immunicum.com
ImmunoCellular (IMUC) to Present at the 16th Annual Meeting of the Society for Oncology
Category Brain, ICT-107, Immune System, vaccination, Vaccine
November 18, 2011
ImmunoCellular Therapeutics Ltd. (OTCBB: IMUC), a biopharmaceutical company developing new therapeutics to fight cancer using the immune system, is taking a different approach than companies like ImmunoGen Inc. (NASDAQ: IMGN) and Immunomedics Inc. (NASDAQ: IMMU) by targeting cancer stem cells (CSCs) to prevent instances of recurrence.
Recently, the company announced that it would be presenting at the 16th annual meeting of the Society for Oncology. The company will give a presentation entitled, “A cancer vaccine targeting cancer stem cell antigens (ICT-107) demonstrates correlated tumor antigen expression and progression free survival and may reduce the cancer stem cell population in recurrent tumors.”
Here’s a copy of the complete press release from ImmunoCellular:
ImmunoCellular Therapeutics, Ltd. (“ImmunoCellular” or the “Company”) (OTCBB: IMUC.OB), a biotechnology company focused on the development of novel immune-based therapies, today announced that John Yu, MD, Chairman of ImmunoCellular Therapeutics, will take part in the 16th Annual Meeting and Education Day of the Society for Neuro-Oncology (SNO) to be held at the Hyatt Regency, Orange County, California from November 17-20, 2011. SNO is the premier professional society comprising neuro-oncologists from across the U.S. and abroad.
The Company’s presentation titled, “A cancer vaccine targeting cancer stem cell antigens (ICT-107) demonstrates correlated tumor antigen expression and progression free survival and may reduce the cancer stem cell population in recurrent tumors,” will be presented at 7:30 p.m. on Friday, November 18, 2011 at the Hyatt Hotel in Orange County, California. It discusses updated data on antigen expression and immune response referencing correlations of increased progression-free survival (PFS) and overall survival (OS) from the Company’s Phase I clinical trial of ICT-107. Of the 16 patients in the study, 6 showed no signs of tumor recurrence, with 3 experiencing no disease progression over 4 years after vaccination, while the other three have been disease free for at least 3 years. The expression of four out of six ICT-107 antigens in the pre-vaccine tumors correlates with prolonged PFS and OS in newly diagnosed GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in patients with recurrent tumors. ICT-107 may thus immunologically target the cancer stem cell population of glioblastoma.
In the Company presentation at the symposium, “Current State of the Art: Vaccine Development In The Treatment of GBM,” on Saturday, November 19, 2011, starting at 12:00 p.m., Dr. Yu will discuss the encouraging prior clinical data for ICT-107, and the ongoing Phase-II double-blind, placebo-controlled, 2:1 randomized study designed to evaluate the safety and efficacy of ICT-107 in patients with newly diagnosed GBM. The study will enroll approximately 160 patients at more than 20 clinical trial centers in the U.S. in collaboration with leading experts and opinion leaders in neuro-oncology.
Manish Singh, CEO of ImmunoCellular Therapeutics, said, “We are excited to participate in this premier gathering of medical professionals specializing in neuro-oncology. We believe that it is a great opportunity to update these specialists to the exciting progress being made in our development of ICT-107.”
About ImmunoCellular Therapeutics, Ltd.
ImmunoCellular Therapeutics is a Los Angeles-based clinical-stage company that is developing immune-based therapies for the treatment of brain and other cancers. The Company recently commenced a Phase II trial of its lead product candidate, ICT-107, a dendritic cell-based vaccine targeting multiple tumor associated antigens for glioblastoma. To learn more about the Company, please visit www.imuc.com.
Forward-Looking Statements
This press release contains certain forward-looking statements that are subject to a number of risks and uncertainties, including the risk that the safety and efficacy results obtained in the Phase I trial for ICT-107 will not be confirmed in subsequent trials. Additional risks and uncertainties are described in IMUC’s most recently filed SEC documents, such as its most recent annual report on Form 10-K, all quarterly reports on Form 10-Q and any current reports on Form 8-K. IMUC undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.
Direct Injection of Vaccine into Pancreatic Tumor Linked to Stable Disease
Category Immune System, Vaccine
Previous studies by scientists at CINJ have shown that injecting a vaccine and other immunity-producing drugs into a cancer tumor itself — rather than the traditional site of the skin — can result in a reversal of the traditional immune blockade and the development of specific immunity to the tumor. This body-wide tumor-specific immunity has the potential of blocking the growth of the original tumor as well as eliminating small deposits of tumor that can cause the cancer to spread. Stemming from this research is a clinical trial that is the focus of this poster presentation. The study by CINJ investigators further tests this vaccine strategy, designed to harness the body”s own immune system to fight cancer.
Researchers are utilizing two types of the investigational vaccine known as PANVAC. PANVAC contains gene additives that might stimulate a person”s immune system to recognize and develop an immune response to the disease. PANVAC-V, which uses the same virus as the smallpox vaccine, is a live but weakened vaccinia vaccine (meaning the virus can still multiply) that is given in the arm. PANVAC-F (a live Fowlpox virus that can not multiply) is injected into the arm and into the tumor itself. Direct tumor injection takes place through a procedure known as endoscopic ultrasound, in which a scope is inserted through the mouth and into the stomach.
During the first phase of the study, which looked at six participants whose cancer could not be removed through surgery, patients were evaluated for toxicity, tumor progression and the presence of tumor markers for pancreatic cancer. Two patients were removed from the study after two weeks due to rapid disease progression. Of the remaining four patients, three had received gemcitabine – a standard treatment for pancreatic cancer – after receiving vaccination treatment. The other patient was treated with gemcitabine, followed by capecitabine and radiation, prior to the vaccination regimen and received no other treatment after.
Of these four patients, all were shown to have clinically stable disease after 15 months, 13 months, 12 months and nine months respectively. The second part of the trial is accruing additional participants, who are being given a higher dosage of PANVAC-F during direct injection of the tumor.
Elizabeth Poplin, MD, medical oncologist at CINJ and professor of medicine at UMDNJ-Robert Wood Johnson Medical School, is the lead researcher on the study, which is sponsored by the National Cancer Institute (NCI). “By utilizing the body”s own defenses in this way in combination with traditional therapies, we have an opportunity to better identify more effective treatment and management options for this disease, which unfortunately only has a five-year, five-percent survival rate,” said Dr. Poplin.
Other investigators include David A. August, Tamir Ben-Menachem, Hazar Michael, and Rene Artymyshyn, CINJ and UMDNJ-Robert Wood Johnson Medical School; James L. Gulley and Jeffrey Schlom, NCI; and Robert S. DiPaola and Edmund C. Lattime, CINJ and UMDNJ-Robert Wood Johnson Medical School.
The work was supported by The NCI Cancer Therapy Evaluation Program and by NCI U01-CA07031 and P30-CA72720.
CINJ members will be among the more than 3,000 academics, scientists and pharmaceutical industry representatives at the meeting to discuss the latest discoveries in molecular biology and how those advances are shaping targeted cancer therapies. The event is open to registered participants.
About The Cancer Institute of New Jersey
The Cancer Institute of New Jersey (www.cinj.org) is the state”s first and only National Cancer Institute-designated Comprehensive Cancer Center dedicated to improving the detection, treatment and care of patients with cancer, and serving as an education resource for cancer prevention. CINJ”s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support CINJ, call 732-235-8614 or visit www.cinjfoundation.org. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School. Follow us on Facebook at www.facebook.com/TheCINJ.
The CINJ Network is comprised of hospitals throughout the state and provides the highest quality cancer care and rapid dissemination of important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. System Partner: Meridian Health (Jersey Shore University Medical Center, Ocean Medical Center, Riverview Medical Center, Southern Ocean Medical Center, and Bayshore Community Hospital). Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Medical Center, Carol G. Simon Cancer Center at Overlook Medical Center, and Cooper University Hospital. Affiliate Hospitals: CentraState Healthcare System, JFK Medical Center, Mountainside Hospital, Robert Wood Johnson University Hospital Hamilton (CINJ Hamilton), Somerset Medical Center, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate
Combination therapy shows potent tumor growth inhibition in preclinical studies
Category Monoclonal Antibody, REGN910
SAN FRANCISCO — Combining the investigational agents REGN910 and aflibercept yielded statistically significant improvements in antitumor effects in animal models compared with either agent alone, according to results presented at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, held Nov. 12-16, 2011.
“These preclinical findings suggest that combining REGN910 (SAR307746) and aflibercept in the clinic could be an attractive approach for future clinical research,” said Alshad S. Lalani, Ph.D., director of strategic oncology development at Regeneron Pharmaceuticals Inc. in Tarrytown, N.Y. “The rationale is that inhibition of tumor angiogenesis by combining antiangiogenesis treatments could translate into more potent and durable antitumor responses than those observed with single-agent therapy.”
In this preclinical mouse study, researchers from Regeneron and BC Cancer Agency in Vancouver, British Columbia, Canada, monitored how REGN910 and aflibercept blocked vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2), which are critical growth factors for tumor angiogenesis, or blood vessel formation.
REGN910 is a fully human monoclonal antibody discovered using Regeneron VelocImmune antibody technology that binds and inhibits Ang2. Aflibercept is a fully human fusion protein that binds all forms of VEGF-A, as well as VEGF-B and placental growth factor. REGN910 and aflibercept are being developed by Regeneron and Sanofi.
In addition, researchers performed tissue analyses to monitor the number of tumor blood vessels, tumor hypoxia (oxygen deprivation), tumor cell death and tumor perfusion.
“When used alone in animal studies, both REGN910 and aflibercept blocked tumor angiogenesis and growth; however, the combination of the two led to increased tumor hypoxia and consequently to the death of a large percentage of the tumor cells,” Lalani said. “Consistent with its ability to promote rapid and widespread tumor cell death in histology, the combination treatment inhibited tumor growth to a significantly greater extent than the single agents in multiple tumor models — colorectal, mammary and prostate. In particular, it caused dramatic tumor regression in the colorectal tumor models. Importantly, no visible evidence of toxicities or enhanced body weight loss was observed following the combination treatment.”
In ongoing animal studies, Lalani and colleagues are studying the reasons behind the results with the combined therapy. They are also investigating biomarkers that will allow them to monitor the combination therapy treatment effect and/or to identify which tumors are most likely to respond to treatment.
Glutamine–increases NK cell activity, decreases PGE2 synthesis, inhibits tumor growth, stabilizes weight loss, and reduces incidence of stomatitis and infection
Category Glutamine, Immune System, Natural Killer Cells
Glutamine–increases NK cell activity, decreases PGE2 synthesis, inhibits tumor growth, stabilizes weight loss, and reduces incidence of stomatitis and infection
Tumors typically have high concentrations of glutamine; thus, physicians have been reluctant to add supplemental glutamine to a cancer protocol. However, oral glutamine (1 gram per kg of body weight a day administered to rats) upregulated tissue glutathione (a powerful antioxidant) by 25% and increased natural killer cell activity 2.5-fold. PGE2 synthesis (a pro-inflammatory prostaglandin that fuels tumor growth) decreased and tumors were inhibited by 40% (Klimberg et al. 1996a).
When glutamine accompanied either chemotherapy or radiotherapy, it protected the host and actually increased the selectivity of therapy for the tumor. This was evidenced among a group of rats (receiving either methotrexate, cyclophosphamide, or cisplatin) whose tumor reduction nearly doubled with glutamine supplementation (Klimberg et al. 1992, 1996b).
Researchers also observed that glutamine decreased progression of tumor formation in rats implanted with mammary tumors, suggesting oral glutamine may be useful as a chemopreventive in breast cancer (Feng et al. 1997). Oral glutamine maintained lymphocyte numbers and protected the gut of esophageal cancer patients during radio/chemotherapies (Yoshida et al. 1998).
Glutamine typically stabilizes weight loss by preserving intestinal function and allowing better nutrient absorption. Subsequently, glutamine prolongs survival by slowing down catabolicwasting, a disorder characterized by weight loss, diminished muscle mass, and loss of body fat. Fewer incidences of stomatitis (a generalized inflammation of the oral mucosa) and bouts of infection help reduce the number of days spent in a hospital (Anderson et al. 1998). Harvard University research showed that glutamine supplementation decreased medical expenses of leukemia patients undergoing bone marrow transplants by $21,095 per patient (MacBurney et al. 1994). (The retail cost of glutamine is $10.00 per day.)
A suggested glutamine dosage is 2 or more grams a day taken on an empty stomach. Glutamine is regarded as nontoxic, but cancer patients contemplating higher dosages should do so only after consulting with a health care provider.
Inositol hexaphosphate (IP-6)–activates natural killer cells, promotes differentiation, supports p53 activity, and normalizes the cell cycle by modifying signal transduction pathways
Category General Cancer Research, Immune System, IP-6
Inositol hexaphosphate (IP-6)–activates natural killer cells, promotes differentiation, supports p53 activity, and normalizes the cell cycle by modifying signal transduction pathways
IP-6, a promising anticancer compound sold as a nutritional supplement, is a combination of inositol (a B vitamin) and phytic acid, also known as inositol hexaphosphate. According to Dr. A. Shamsuddin, M.D., Ph.D., who introduced IP-6 after more than 15 years of research, it works by enhancing the body’s ability to defend itself against cancer, making it of equal importance as either a cancer preventive or therapeutic agent.
Inositol hexaphosphate is a sugar, very much like glucose, except it has six phosphates attached to its molecules. Every animal and plant species tested had varying levels of IP-6, but the highest amounts were found in rice, about 2% by weight: 100 grams of rice provide approximately 2 grams of IP-6, but even that amount is not readily available. Since the body is dependent upon digestive enzymes to break it down, only a meager amount is actually absorbed from foodstuffs. Thus, IP-6 in encapsulated or bulk forms should be of special interest to cancer patients and those desiring protection against cancer.
The following chemotherapeutic properties are assigned to the immune modulator:
- IP-6 activates natural killer cells, cells that work without antibody participation (Baten et al. 1989).
- IP-6 decreases cellular proliferation (Sakamoto et al. 1993; Shamsuddin et al. 1989b). Illustrative of its potential, IP-6 reduced large intestinal cancer (by regulating cell proliferation) in F344 rats even when the treatment was begun 5 months after carcinogenic induction (Shamsuddin et al. 1989a).
- IP-6 promotes differentiation (“normalization”) of cancer cells, that is, an unspecialized, atypical cell structure assumes the likeness of the tissue of origin, indicating the virulence of the malignancy is waning (Yang et al. 1995). IP-6 was shown to inhibit growth and induce differentiation in HT-29 human colon cancer cells, making it valuable as an adjunctive treatment in colon cancer. IP-6 also strongly inhibited growth and induced differentiation in human prostate cancer cells (PC-3) in both in vitro and in vivo studies (Shamsuddin et al. 1995).
- IP-6 has been effective against every cancer cell tested (Shamsuddin et al. 1997; Grases et al. 2002).
- After inducing cancer in laboratory animals, IP-6 administered either orally or by injection at the site of the tumor, or intraperitoneally, resulted in tumors two-thirds smaller than the controls. As tumors reduced in size, survival rate increased (Shamsuddin et al. 1989a).
- IP-6 increases expression of the tumor suppressor gene p53 by up to 17-fold. p53 acts on cells under stress, such as those with DNA damage, reducing proliferation and encouraging apoptosis. When cancer arises, a mutation in p53 is commonly involved. Lastly, since loss of p53 function increases cancer cells’ resistance to chemotherapeutic agents, the stimulating action of IP-6 on p53 makes it an attractive adjuvant chemotherapeutic agent (Shamsuddin et al. 1997; Saied et al. 1998).
Toxicity studies (dating back to 1958) showed that a daily dose of 9 grams of IP-6 for 3 years resulted in side effects, including lesser incidences of kidney stones and fatty liver, as well as lower cholesterol levels. It is important to note that IP-6 does not kill cancer cells, as most anticancer agents do; thus, hair loss and immune suppression do not occur. A suggested dosage of 1-3 grams a day is adequate for most individuals. For those requiring larger doses, a powder is available (1 scoop twice daily is equivalent to 16 capsules, supplying about 6.4 grams of IP-6).
A New Cross-Species Study Points to Chronic Inflammation As An Impediment To Anti-Cancer Treatment, Say Nutri-Med Logic Corp.
Category Chemotherapy, Immune System, Inflamation, Molecular, nuclear factor-κB (NF-kB), P53 gene, PTEN, Tumor suppressor
Sunday, October 16, 2011
Expanding on this newly published study, Nutri-Med Logic Corp says that while clinical inflammation has a tumor restraining role, chronic inflammation not only opposes anti-cancer treatments, but it also permits cancer cells to escape repair or destruction.
Miami. Florida (PRWEB) October 16, 2011
Nutri-Med Logic Corp: Inflammation vs. Inflammation.
According to newly published study, the enhanced activity of a protein inside all cells, called nuclear factor-?appa B (NF-?B), causes resistance to chemotherapy. However, overwhelming number of studies have concluded that the same protein (NF-kB), at normal levels, confers tumor suppressing properties.
NF-kB is the master switch of inflammation in the body. Inflammation is an immune mechanism, as the matter of fact without inflammation there would be no immune activity. While clinical (acute) inflammation protects the body, even against formation of cancer cells, but the chronic (excessive) inflammation not only promotes cancer but also many degenerative diseases.
A cancer cell is any cell that its genetic formula has changed and, additionally, it has gained the ability to divide (proliferate) at a much faster rate than normal cells. Cancer cells do not follow the system, but retain the same knowledge of survival (genetic information) as the normal cells in the body and, thus, capable of manipulating the system for their survival and the survival of its offspring (daughter cancerous cells).
If successful in multiplying, they form a cluster and having the knowledge of the genetic formula, they cause formation of blood vessels (Angiogenesis) inside the cluster and thus form a tumor; an organ that was not put in place by design rather by defect. If the tumor could not be destroyed then the cancer cells will enter blood or lymph system and colonize (metastasis) and the cancer becomes terminal.
The human body has many checkpoints to insure that when a cell divides, the daughter cell has a correct genetic formula and that it will follow the system. Amongst such checkpoints, two proteins stand out by themselves: p53 and PTEN, which are made by genes of the same names. These two genes are also called Tumor suppressor genes and not withstanding many other factors (i.e. histone deacetylation, virus or gene deletions, etc.), chronic inflammation inactivates p53 and redox imbalance (oxidative stress) inactivates PTEN.
PTEN and P53 slow down the division of defective cells so that repair (Base Excision) would be done. If repairs cannot be done then an instruction for apoptosis (self-destruction) is given. If apoptosis fails then it would be unlikely for the immune system to stop the multiplication of cancer cells, as they divide at rate much faster than immune system could eliminate.
The cancer cells use the excessive reactive oxygen species (Redox Imbalance) to deal with PTEN and utilize chronic inflammation, via over-activation of NF-kB, to trigger an anti-apoptotic mechanism to sustain their survival and multiply, since the hyperactivity of NF-kB blocks (inhibits) the activation of p53.
Down-regulation (lowering the activity) of NF-kB is required for the p53 to instruct apoptosis, or in another word, instructions for self-destruction of unrepairable defective cell(s).
Since the activation of p53 would result in repairs or apoptosis (auto-destruction), then the inactivation of p53 equates to bypassing one of the most important checkpoints and the subsequent survival of defective cell(s). (2,3)
While, at the normal level (homeostatic), both reactive oxygen species and inflammation are assets to the immune system but their excessive levels are liabilities.
Nutrients have the ability to enhance or slowdown the inflammatory processes more specifically two polyunsaturated fatty acids: Omega-6 and Omega-3, both of which are transported to the body through diet.
Omega-6 produces metabolites for sole purpose of enhancing and sustaining inflammation. Omega-3 produces metabolites to Resolvin resolve the inflammation in the body (Resolvin-E and Resolvin-D), which help in moderating the inflammation.
As the matter of fact, studies have established a way to moderate NF-kB is through suitable dietary ratio of Omega-3/Omega-6. (1)
Needless to say that oxidative stress could also be moderated via anti-oxidant food.
While it would be very imprudent to state that nutrients could prevent the formation of cancer or stop its progression but, without a doubt, any nutrient or food that could interfere with the mechanism that cancer cells utilize, to survive and/or multiply, do matter. Anti-inflammatory and anti-oxidant nutrients help to moderate inflammation and oxidative stress, thus are very important.
In conclusion, Nutri-Med Logic Corp agrees with the this recent study but adds that not only chronic inflammation but also oxidative stress play a key role in pathogenesis and progression of cancer.
Nutri-Med Logic Corp (www.nutrimedlogic.com) is a producer of dietary supplements such as:
A Concentrated and Balanced Omega-3 having the same concentration of EPA and DHA, 50% 50%. DHA of Omega-3 is very beneficial for moderating inflammation in brain, nervous system and helps to moderate stress. EPA of Omega-3 is very beneficial in moderating the inflammation in the cardiovascular system.
R-Alpha Lipoic Acid, a potent anti-oxidant food for combating oxidative stress. R-Alpha lipoic is made and known by the human body;
Poly-Enyl-Phosphatidylcholine, an ideal dietary supplement for liver and intestine.
Nutri-Med Logic’s products are Formulated Based on Nutritional Logic, made from the highest quality raw materials that are manufactured in pharmaceutical facilities, encapsulated in pharmaceutical facilities and packaged in pharmaceutical facilities.
It must be noted that the studies, sources or statements, herein, have not been evaluated by The FDA and, thus, one should not relate the cause of any diseases, stated herein, to lack of the supplements stated above; nor equate their supplementation to prevention, treatment or cure.
1. Biochemical Biophysical Research. 1996 Dec 13;229(2):643-7.
2. EMBO J. 2003 October 15; 22(20): 5501-5510.
3. Biochemical pharmacology 72 (2006)1605-162
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For the original version on PRWeb visit: www.prweb.com/releases/prweb2011/10/prweb8882211.htm
Three Cancer Research Institute Scientists to Receive 2011 Nobel Prize in Physiology or Medicine
Category Finance and Politics of cancer research and treatment, Immune System
Source: Cancer Research Institute
Bruce Beutler, Jules Hoffmann, and Ralph Steinman to Receive Top Award in Science
Newswise — The Nobel Foundation announced yesterday that three immunologists will receive the 2011 Nobel Prize in Physiology or Medicine for their fundamental discoveries on immune system recognition of infection. Drs. Bruce Beutler, chairman of the department of genetics at The Scripps Research Institute, and Jules Hoffmann, research director for the National Center of Scientific Research in France, will share one-half the prize, and Dr. Ralph Steinman, a professor of cellular physiology and immunology at The Rockefeller University, will receive the other half.
Sadly, concurrent with the award announcement yesterday the world also learned that Dr. Steinman passed away on Friday after a long battle with pancreatic cancer. The Nobel Foundation has decided to bestow the award posthumously on Dr. Steinman.
All three scientists have long and strong connections with the Cancer Research Institute, and we therefore take great pride in this superlative honor, which reflects both on the important contributions these individual scientists have made as well as on the prominence of immunology and, increasingly, tumor immunology, in the advancement of new approaches to the prevention and treatment of infectious diseases and cancer.
William B. Coley Award to Nobel Prize Winners
The three Nobel Prize winners are former recipients of the Cancer Research Institute’s top scientific honor, the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology (Steinman in 1998, Hoffmann in 2003, and Beutler in 2006). CRI honored Dr. Steinman for his discovery of the dendritic cell, a fundamental immune system cell responsible for alerting other components of the immune system to danger from infection and cancer. Drs. Beutler and Hoffmann received the Coley Award for their independent work in identifying the toll receptor (Hoffmann in fruit flies) and toll-like receptor gene (Beutler in mammals) involved in the activation of the innate immune response. Beutler, Hoffmann, and Steinman join the list of other past Coley Award recipients who have since gone on to receive the Nobel Prize and other major scientific awards, underscoring the Coley Award selection committee’s foresight and the award’s significance as a predictor of future recognition by others outside the fields of immunology or tumor immunology.
Direct CRI Funding to Nobel Prize Winners
Ralph Steinman:
In 1980, CRI supported Dr. Steinman’s first study on the potential for dendritic cells to orchestrate immune attack on tumors. It was his first tumor immunology study, proposed at a time when few believed that the immune system could be trained to fight cancer. CRI continued to support Dr. Steinman’s lab by awarding postdoctoral fellowships to two scientists in his laboratory, Dr. Jonathan Austyn (currently a professor of immunobiology and principal investigator in the dendritic cell research group at Oxford University John Radcliffe Hospital) and Dr. Angela Granelli-Piperno (who has since published work on HIV infection in dendritic cells and the role of lymphokines in autoimmune disorders). CRI’s seed support of Dr. Steinman’s then highly unconventional idea laid the foundation for his future studies on dendritic cell vaccines for cancer.
In 1998, CRI awarded Dr. Steinman a grant to support a preclinical study of active immunotherapy against lymphoma by antigen-presenting dendritic cells. Such vaccines have since become a major focus of research and development, and Provenge™, the first FDA-approved therapeutic cancer vaccine for prostate cancer, is based on the dendritic cell vaccine technology Dr. Steinman pioneered. It has been reported that Dr. Steinman himself was a patient in a study of his own dendritic cell vaccine for pancreatic cancer, and he credited the vaccine with extending his life.
Jules Hoffmann:
Dr. Hoffmann’s exploration of the innate immune system and its activation bears central importance to CRI’s ongoing efforts to determine optimal vaccination strategies in the treatment of cancer. A critical step in successful vaccination is stimulation of the non-specific (innate) immune system—first-line responders to infection and damaged cells that provide broad protection against bacteria and fungi and also play an important role in the activation of cancer-specific (adaptive) immunity.
In addition to the 2003 Coley Award, CRI provided postdoctoral fellowship support to Dr. Hoffmann’s laboratory in 1995, to Dr. Sarah Ades for her work to clone and characterize the lipopolysaccharide pattern recognition receptor in the innate immune response of fruit flies (drosophila). Dr. Ades is currently an associate professor of biochemistry and molecular biology at Pennsylvania State University.
Bruce Beutler:
Dr. Beutler took Dr. Hoffmann’s work in the fruit fly and found the corresponding innate immune system receptor in mammals, bringing Hoffmann’s important discoveries to bear on the treatment of human disease. The Beutler lab has received CRI funding in the form of postdoctoral fellowships for Dr. Carrie N. Arnold (2007) and Dr. Amanda L. Blasius (2008), to support their respective studies of mammalian resistance to viral infection and genetic analysis of the type 1 interferon response to toll-like receptor 9. CRI also funded two members of Dr. Beutler’s lab in 2006 (Dr. Kasper Hoebe and Dr. Zhengfan Jiang) in their genetic analysis of “cancer proof” SR/CR mice from the laboratory of Dr. Zheng Cui.
We congratulate Drs. Beutler and Hoffmann on their outstanding accomplishment, and extend our congratulations to Dr. Steinman’s family as well as our condolences on their loss of a beloved family member, who was also a highly respected colleague and long-time friend of tumor immunology and the Cancer Research Institute.
References:
Nobel Foundation News Release Announcing the 2011 Nobel Prize in Physiology or Medicine
Interview with Dr. Steinman in The Researcher, a publication of the Cancer Research Institute
About the Cancer Research Institute
The Cancer Research Institute (CRI), established in 1953, is the world’s only nonprofit organization dedicated exclusively to transforming cancer patient care by advancing scientific efforts to develop new and effective immune system-based strategies to prevent, treat, and cure cancer. Guided by a world-renowned Scientific Advisory Council that includes three Nobel laureates and thirty-one members of the National Academy of Sciences, CRI has invested more than $200 million in support of research conducted by immunologists and tumor immunologists at the world’s leading medical centers and universities, and has contributed to many of the key scientific advances that demonstrate the potential for immunotherapy to change the face of cancer treatment.
To accelerate the pace of progress in the field, CRI convenes and coordinates global collaborations among academics, industry scientists and decision makers, regulatory representatives, and health research associations focused on discovery, development, and refinement of new cancer immunotherapies. A founding visionary and scientific leader in tumor immunology, CRI is helping to shape the emerging field of immuno-oncology, and is ushering in a new era of medical progress to bring more treatment options to cancer patients sooner.
The Cancer Research Institute has one of the lowest overhead expense ratios among nonprofit organizations, with more than 85 percent of its resources going directly to the support of its science, medical, and research programs. CRI meets or exceeds all 20 standards of the Better Business Bureau Wise Giving Alliance, the most comprehensive U.S. charity evaluation service, and has earned the GuideStar Exchange Seal, indicating our commitment to the transparency of our organizational information to donors, funders, those we serve, the public, and regulators. CRI has also received an ‘A’ grade for fiscal disclosure and efficiency from the American Institute of Philanthropy, as well as top accolades from other charity watchdog organizations. For more information, visit http://www.cancerresearch.org.
