Defeat Osteosarcoma » Vaccine Studies

activation of antitumor cytotoxic T lymphocytes by fusion of patient-derived dendritic cells with autologous osteosarcoma

James Street — Wed, 14 Dec 2011 01:59:39 +0000

Experimental Oncology 27, 273-278, 2005 (December)

273

Z. Yu*, B. Ma, Y. Zhou, M. Zhang, X. Qiu, Q. Fan

Center of Orthopedic Surgery Orthopedics Oncology Institute of Chinese PLA, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, Shaanxi, China

Background and Aim: Fusion of human dendritic cells (DCs) with tumor cells is an effective approach for delivering tumor antigens to DCs, and DC/tumor fusion cells are potent stimulators of autologous T cells. However, the integration and morphology of DC/osteosarcoma fusion cells has not been examined. This study was designed to investigate the antitumor effects of tumor

vaccine produced by electrofusion between human osteosarcoma cells and DCs. Methods: In the present study, we eletrofused patient-derived DCs to autologous osteosarcoma cells. The fusion cells possessed the properties of both patient cells. After electrofusion, the cytoplasm of the two cells was integrated, whereas their nuclei remained separate entities. The intracellular structure

was observed on fusion cells under the transmission electron microscope. Results: Coculture of patient-derived peripheral blood mononuclear cells (PBMC) with DC/tumor fusion cells resulted in activation of T cells as assessed by standard cytotoxic T lymphocytes (CTLs) assays.

Conclusions: The present study provides valid evidence on integration of human DCs and tumor cells and links their properties to T cell activation. The fusion cells may thus represent a promising strategy for DC-based immunotherapy of patients with osteosarcoma.

Key Words: dendritic cell, osteosarcoma, fusion cell, T cell activation, immunotherapy, cytotoxic T lymphocytes, autologous

Dendritic cells (DCs) are the best professional anti-

gen-presenting cells (APCs) and they have been used

extensively in this context because they can increase the

surface expression of major histocompatibility complex

(MHC) antigens of class I and class II, and co-stimulatory

molecules (required for efficient presentation of pep-

tides and stimulation of T cells) [1] and can synthesize a

variety of immunologically important cytokines such as

IL-1, TNF-α, and IL-12. Therefore, DCs have been used

in humans to enhance antitumor immunity by stimulating

the immune system to recognize and destroy malignant

cells. Methods for delivering tumor antigens into DCs are

the focus of intensive investigation in DC-based tumor

vaccines. These include introduction of identified tumor

antigens into DCs by pulsing with peptides or proteins and

transfecting with RNA or DNA [2–6]. In preclinical models,

these DC-based vaccines have induced protective and

therapeutic immune responses against tumors. In clinical

trials, vaccination with lysate- or idiotype-pulsed DCs has

resulted in immunologic and clinical responses [7–11].

Another evolving strategy is the use of fusion

constructs between DCs and tumor cells. With this

technique, an immunogenic hybrid cell can be created

with the properties required for initiation of primary

antitumor immune responses. Theoretically, fusion

of DCs with tumor cells will result in the presentation

of a broad spectrum of tumor antigens, both known

and unidentified, in the context of the potent immune-

stimulatory machinery of the DCs. Indeed, vaccination

of mice with fusion cells has induced protective and

therapeutic antitumor immunity [12–14].However, the

traditional fusion method using polyethylene glycol

(PEG) is often plagued by its too widely ranging ef-

ficiencies, toxicity, poor reproducibility, and varying

susceptibilities among individual tumor cell partners.

Recently an alternative means of generating DC-tu-

mor hybrids by exposing cells to electric fields has been

described. The success of fusion has unequivocally been

verified by a number of analyses including FACS, cytospin,

confocal immunofluorescence, and DNA content. The ef-

ficiency of electrofusion is usually ten to hundreds times

higher than the chemical methods [15–17]. However,

little is known yet about the fusion process, fusion cell

morphology, and the relation between antigen presenta-

tion of fusion cells and induction of antitumor immunity.

The tasks of the present study was to fuse osteosarcoma

cells from patients with bone cancer with autologous DCs,

evaluate an integration of human DCs and tumor cells and

link their properties to T cell activation.

Materials and Methods

Generation of DCs from peripheral blood

mononuclear cells (PBMC). Mononuclear cells

were isolated from the peripheral blood of patients

with osteosarcoma by Ficoll/Hypaque density gradi-

ent centrifugation. The PBMC were cultured in RPMI

1640 medium containing 1% autologous serum for

1 h. The nonadherent cells were removed, and the

T cells were purified by nylon wool separation. The

adherent cells were cultured for 1 week in RPMI 1640

medium containing 1% autologous serum, 1000 U/ml

GM-CSF, 500 U/ml IL-4 and 1000 U/ml recombinant

human tumor necrosis factor-α (TNF-α) (all cytokines

from R&D Systems, USA), to generate DCs. Then the

nonadherent and loosely adherent cell clusters of

proliferating DC were harvested.

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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Scientists Discover Potential Strategy To Improve Cancer Vaccines

James Street — Fri, 24 Dec 2010 17:22:31 +0000

17 Dec 2010

The promise of vaccines targeted against various types of cancer has raised the hopes of patients and their families. The reality, however, is that these promising treatments are difficult to develop. One of the challenges is identifying a discrete cellular target to stop cancer growth without inactivating the immune system. Scientists at UNC Lineberger Comprehensive Cancer Center report a laboratory finding that has the potential to increase the effectiveness of therapeutic cancer vaccines.

The team found that the absence of the function of a protein called NLRP3 can result in a four-fold increase in a tumor’s response to a therapeutic cancer vaccine. If this finding proves consistent, it may be a key to making cancer vaccines a realistic treatment option. Their findings were published in the journal Cancer Research.

Jonathan Serody, MD, a study author, explains, “This finding suggests an unexpected role for NLRP3 in vaccine development and gives us a potentially pharmacologic target to increase vaccine efficacy.”

The research team was headed by co-leaders of the UNC Lineberger Immunology Program: Serody, MD, an expert in tumor immunology, and Jenny Ting, PhD, a pioneer in understanding the NLR family of proteins. Serody is the Elizabeth Thomas Professor of Hematology and Oncology. Ting is UNC Alumni Distinguished Professor of Microbiology and Immunology and director of the Inflammation Center at UNC.

The team discovered that deleting the NLRP3 proteins reduced the supply of a tumor-associated cell called myeloid-derived suppressors, making them five times less effective in reaching the site of tumor growth. Researchers working with Serody had previously shown that these myeloid cells are critically important as they allow the tumor to evade a beneficial immune response. This finding is the first to link immature myeloid cells, NLRP3, and the response to cancer vaccines.

Serody says, “We had originally thought inactivating the NLRP3 protein would decrease the immune system’s ability to respond to cancer because NLRP3 is important in alerting immune cells to changes in the environment the immune response to cancer. Instead what we found was that by inactivating these proteins, the tumor vaccine was made more effective because fewer myeloid-derived suppressor cells were available to promote tumor growth and reduce the efficacy of the vaccine.”

At present, there is only one FDA-approved cancer vaccine called Provenge, used to treat advanced prostate cancer. Provenge has been shown to extend survival by three to four months.

Vaccines are difficult to make. Because a vaccine is person-specific, made with the individual’s immune cells, the production process requires that the individual’s cells are isolated and shipped to the company for vaccine production. As a result, the vaccines are expensive. Provenge costs approximately $100,000 for three treatments.

“A vaccine is not like a pill that can be manufactured in bulk,” Serody explains. “And, it’s not like developing a vaccine against a virus such as polio or smallpox. Cancer cells look a lot like regular cells, so it is hard to trick the body into thinking cancer cells are ‘foreign.’ Our hope is that our findings and future work in this area will enable us to develop more effective vaccines against many types of cancer. ”

Other UNC authors are Hendrik W. van Deventer, MD, assistant professor of medicine; Joseph E. Burgents, former UNC graduate student, now a postdoctoral fellow at the National Institute of Environmental Health Sciences; Qing Ping Wu, research specialist; Rita-Marie T. Woodford, research assistant in the UNC School of Dentistry; W. June Brickey, research assistant professor of microbiology and immunology; Irving C. Allen, PhD, postdoctoral fellow, UNC Lineberger; and Erin McElvania-Tekippe, former UNC graduate student, now a postdoctoral fellow at Washington University in St. Louis.

Source:
Dianne Shaw
University of North Carolina School of Medicine

Article URL: http://www.medicalnewstoday.com/articles/211722.php

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Dr. Patrick Moore explains cancer-causing viruses to Laureate Society

James Street — Sun, 05 Dec 2010 06:22:16 +0000

By Carolyn SusmanSpecial to the Daily News

Updated: 8:46 p.m. Saturday, Dec. 4, 2010

Posted: 6:07 p.m. Saturday, Dec. 4, 2010

Dr. Patrick Moore looked out at the people dining with him at Café Boulud and delivered a shocking statement. He had been talking about a virus that causes a rare skin tumor: “About everybody in this room is infected with it,” he said.

Those enjoying the luncheon for the American Cancer Society’s Laureate Society took note.

The “it” he was referring to is the Merkel cell polyomavirus, which was discovered in his lab at the University of Pittsburgh in 2008 and causes most Merkel cell carcinomas.

But he told everyone to relax. Although this virus is common, the skin cancer tumors that are caused by it are “relatively rare.” He thought it would be of interest to this group of Cancer Society supporters, he said, because factors such as aging, sun exposure and immune suppression are key to the tumor development.

The more widely known skin cancer, melanoma, is much more common, but the Merkel cell carcinoma, he said, is “far more dangerous.”

Moore, together with his wife, Dr. Yuan Chang, is responsible for discovering the viral causes of four human cancers. Among them, and perhaps best known among their work, was identifying and isolating, in 1994, the Kaposi’s sarcoma-associated herpesvirus, which causes this epidemic cancer among HIV/AIDS patients.

He and his wife focus their research on the link between viruses and cancer, a link that was considered tenuous, he said, until very recently.

“Until you know the cause, your hands are tied,” he said. “Otherwise, it’s ‘Katy bar the door.’” Meaning, he said, it’s full speed ahead when that piece of the puzzle falls into place.

He mentioned that, all told, there are seven viruses — “all very different in their behavior” — that cause human cancers. The human papillomavirus (HPV) is one of them. The most common sexually transmitted virus in the United States, according the Centers for Disease Control, HPV is a cause of cervical cancer, as well as several other genital cancers.

Several women in the audience were interested in why the newly available vaccine against this virus is recommended only for young people.

Moore explained that these vaccines are preventive, but the virus — which usually resolves on its own in adults — is already there in many adults once they are sexually active.

Find this article at:

http://www.palmbeachdailynews.com/news/dr-patrick-moore-explains-cancer-causing-viruses-to-1099485.html

Colorectal vaccine developed

James Street — Sat, 27 Nov 2010 04:42:42 +0000

Posted on 26/11/2010 in Scientific Developments/Breakthroughs

Researchers at Dartmouth University have developed a new process for creating a personalised vaccine, which could help patients with colorectal cancer develop an immune response against their tumours.

The study, which was detailed in the Clinical Cancer Care research journal, highlighted that the newly-developed dendritic cell vaccine could prevent the growth of additional metastases if used after surgical resection of metastatic tumours.

Over the course of the research, 26 patients who had tumours removed were given the vaccine a month after surgery and followed for 5.5 years. It was noted that over 60 percent of patients had experienced T-cell immune responses being induced against the patient’s tumour.

Five years after the procedure, 63 percent of the patients who developed an immune response were tumour-free, compared to 18 percent who had not experienced the response.

Commenting on the findings, Dr Richard Barth Jr, chief of general surgery at Dartmouth-Hitchcock Medical Center, said that they suggest a new way to approach cancer treatment.

“Basically, we’ve worked out a way to use dendritic cells, which initiate immune responses, to induce an antitumor response,” he added.

According to figures from Cancer Research UK, in 2007 there were 38,608 cases of colorectal cancer in the UK.

BioTech’s Unprecedented Vaccine Gets Mayo Clinic Nod

James Street — Thu, 18 Nov 2010 04:44:44 +0000

‘Elegantly Simple’ Cancer and Infectious Disease Vaccine Uniquely Addresses Problems Found with Earlier Immunotherapy Approaches

TapImmune and Mayo Clinic to start clinical development of pioneering biotechnology vaccine; Company’s immunotherapy innovation spurs remarkably aggressive immune response, offering broad reaching therapeutic possibility

Seattle-based biotechnology innovator TapImmune Inc. (OTCBB:TPIV) is on to something big. Very big. The company has engineered a remarkable, yet elegantly simple, way for the body to recognize tumor and infectious disease cells and provoke an aggressive immune response whereby the body’s own killer T-Cells attack and eradicate harmful foreign bodies. This with respect to any form of cancer or disease via a technology that’s entirely non-discriminate in helping the body eradicate dangerous cells of many kinds.

Underscoring the vast potential of TapImmune’s approach is its exclusive licensing option agreement with the Mayo Clinic for a breast cancer antigen technology complementary to the company’s TAP (AdhTAP) protocol. In a novel approach, TapImmune and the Mayo Clinic will co-develop a specialized vaccine for patients with very aggressive HER2/neu breast cancer. What’s unique is that TapImmune’s technology actually re-activates the body’s own immune system, triggering mission-critical self-curative mechanisms that would otherwise not function properly.

“We chose to work with the Mayo Clinic because they have great clinical expertise in breast cancer, and we’re focusing specifically on HER2/neu breast cancer because we found complementary technology with Mayo that will work with TAP and address the problems found with earlier approaches,” explains Dr. Glynn Wilson, chairman and CEO of TapImmune. “Importantly, we’re able to work with a leading expert on breast cancer vaccines, Dr. Keith Knutson of the Mayo Clinic, who will conduct the trials. Through these trials, we’ll also address a huge clinical need for patients who express low to moderate levels of HER2/neu and are not candidates for treatment with Herceptin(R) (trastuzumab), an intravenously delivered monoclonal antibody.”

How it Works Simply put, TAP (transporters associated with antigen processing) plays a major role in the complex human immune system. When foreign bodies (viruses and disease) attack cells in the body, the normal response is for killer T-cells to find those invaders and destroy them. TAP is a transporter that helps trigger an immune response by providing a pathway for tumor antigens to be expressed on the surface of the cell. In most solid cancers TAP levels are greatly reduced, which prevents the antigen presentation required to stimulate T-cells into action.

In the treatment of cancer, TAP is analogous to turning on the light bulb on the surface of tumor cells, allowing immune cells to “see” them and inspire action accordingly. For infectious disease treatment, TAP turns the light bulb to a higher intensity to prompt more immune cells to act. TAP potentially allows the immune system to see everything that’s foreign on the surface, in contrast to other approaches that simply focus on a single tumor antigen to try and raise an immune response. Indeed, TapImmune’s technology is entirely unique in that it isn’t dependent on genetics like other immunotherapies and doesn’t directly target the tumor cells, but instead assists the body’s own immune system to do what it was designed to do by turning the TAP back on and activating destroyer T-Cells into “kill” mode. See a more detailed explanation of the science of TAP below.

TAP and Breast Cancer Wilson says with any vaccine, there are two requirements needed to create a good immune response: 1) stimulate the cytotoxic lymphocyte (Class 1 pathway) and 2) stimulate the pathway that stimulates the T helper cells (Class 2 pathway), which gives a long-lasting immune response. The failure to satisfy both of these requirements is one of the reasons other breast cancer vaccines haven’t progressed.

“For breast cancer, we are developing a unique multi-component vaccine that stimulates the Class 2 pathway (CD4 – helper cells) for a prolonged immune response and the Class 1 pathway (CD8 – cytotoxic T cells) to activate killer T-cells that will infiltrate and destroy tumor cells. The HER2/neu vaccines that had been tested in the past either do not stimulate sufficient cytotoxic T-cell response on the Class I pathway or they do not give a long-lasting effect. I realized that we have the capability here with the Mayo technology plus TAP of creating good responses on both sides of the immune system required for a good vaccine. It is a very innovative, creative and exciting approach.”

TapImmune President and CFO Denis Corin agrees. “I think there are a lot of vaccine candidates that have gone through the mill and probably failed at Phase 2 or Phase 3 predominantly because the immune recognition and immune stimulation hasn’t been as effective as they needed it to be to come up with an end-level product. TAP is elegantly simple and we believe applicable across multiple types of cancers.”

“In the overall vision of the use of cancer vaccines, the ultimate goal is to have vaccines that can be used prophylactically at the earliest detection of pre-cancerous conditions like DCIS,” Corin continues. “It is thought that the more advanced the cancer, the lower the TAP levels will be. TAP may be applicable to all stages of cancer if we consider experiments that treated smallpox, augmenting the normal levels of TAP and making a smallpox vaccine fully 100 to 1,000-fold more potent.”

The Science The immune system distinguishes normal and cancerous (or virus-infected) cells by monitoring major histocompatibility complex (MHC) class I, a molecule on the cell’s surface. Nearly all cell types display MHC class I antigen on their surface, continually providing information to the immune system. The MHC molecule, which contains small protein fragments (peptides), cycles to the surface of the cell to present foreign antigens to the cellular immune system, thereby activating the cytotoxic T-cells to kill virus-infected or cancerous cells.

In many cancers, there is a disruption in the process and the MHC on the cell surface is missing the tumor antigen peptides that identify the cell as being cancerous. They are basically hidden from the immune system and grow into tumors that eventually kill the person. Because TAP is affected negatively in the disease process, TapImmune’s vaccine technology turns TAP back on, supplying peptides to the MHC class I molecule. TAP facilitates the binding of foreign peptides to the MHC class I molecule. TAP facilitates the binding of foreign peptides to the MHC class I complex, displaying them on the cell’s surface. Cytotoxic T-cells recognize them as foreign and ultimately neutralize and destroy abnormal cells.

Clinical studies on melanoma when examining primary and metastatic (spreading) tumors show a clear and significant correlation between TAP expression and survival.

The History & Future of TAP Technology TapImmune (formerly GeneMax) was formed in Vancouver, British Columbia, in the laboratories of immunologist Wilfred Jeffries.who with his colleagues produced exciting data showing that administration of TAP to replace deficient levels in tumors or augment natural levels in viral disease had significant therapeutic effects in animal models. Four years ago, TapImmune principals acquired the technology and intellectual property outright from the university and set out to put together a board of directors and advisory board that understands the technology and its potential and to partner with credible collaborators like the Mayo Clinic and Aeras Global TB Vaccine Foundation, an organization largely funded by the Gates Foundation.

“In discussions with Aeras Global TB Vaccine Foundation, we identified the potential of TAP for use in the joint development of their next-generation TB vaccine,” said Denis Corin, TapImmune’s president and CFO. “But you could also look at influenza, SARS, HIV H1N1 and many other societal pathogens. We’re also working with Dr. Poland and the Mayo Clinic on a new small pox vaccine. But, small pox is the tip of the iceberg. There are a number of nasty viruses that are potential bioterrorism threats and governments around the world could stockpile our TAP vaccine and call on it in the event of a bioterrorist threat.”

TapImmune’s TAP technology has the ability to complement most current immunotherapy approaches in a current estimated $21 billion market (Global Vaccine Market Outlook (2007-2010), Research & Markets). And, cancer vaccines will become a major player in the vaccine market, expected to be more than $8 billion by 2012. About TapImmune, Inc. Taplmmune Inc. (OTCBB:TPIV) is a biotechnology company specializing in the development of innovative cell based immunotherapeutics and vaccines in the areas of oncology and infectious disease. The Company’s lead product candidate, the AdhTAP vaccine is designed to restore and augment antigen presentation and subsequent recognition and killing of cancer cells by the immune system. The Company is currently planning the development AdhTAP for the commencement of clinical manufacturing and toxicology studies. The Company is also developing TAP- based prophylactic vaccines. As a vaccine component, the TAP technology has the potential to significantly improve the efficacy of current prophylactic vaccines and enhance the creation of new ones in the fight against pandemic infectious diseases. Learn more online at www.TapImmune.com.

CONTACT: Merilee Kern, 858-577-0206, merilee@kerncommunications.com

Epeius Biotechnologies Reveals a New Generation of Tools for Medical Gene Delivery

James Street — Tue, 16 Nov 2010 07:57:10 +0000

Posted By Tabitha Berg
On Wed, 08 Oct 2008 @ 15:58:16 +0000 UTC
In California,Medical,News: Pharma,Newsdesk | Comments Disabled

SAN MARINO, Calif. — Epeius Biotechnologies Corporation today announced the publication of another landmark paper describing recent technological advances in medical gene delivery. The latest scientific paper, entitled “Targeting metastatic cancer from the inside: A new generation of targeted gene delivery vectors enables personalized cancer vaccination in situ,” was published in the October issue of the International Journal of Oncology (IJO). The paper describes the new state-of-the-art in tumor-targeting biotechnology, nanotechnology, and therapeutic gene delivery developed for clinical applications in the field of oncology. The paper lays the scientific, preclinical and clinical foundations for new applications of personalized medicine, specifically for patients with metastatic cancer.

Based on recent breakthroughs in pathotropic (or disease-seeking) tumor targeting technologies, a new generation of anti-cancer agents is currently being developed. Anti-cancer agents such as Rexin-G can be delivered by simple intravenous infusion, yet are designed to seek out and accumulate in primary and metastatic lesions that have spread throughout the body. Rexin-G is essentially a pathotropically targeted nanoparticle of genetic medicine that is guided by a proprietary targeting technology and is designed to deliver a killer-gene selectively to tumor cells and their associated (proliferative) blood supply.

Representing the first and so far only targeted genetic medicine proven to be both safe and effective in the clinic, Rexin-G is commercially available in the Philippines — for use in all solid tumors that are refractory to standard chemotherapy — and is currently in clinical trials in the USA for several cancer indications.

Following the validation of its lead product in the clinic, Epeius Biotech has developed a second tumor-targeted anti-cancer agent, named Reximmune-C, designed to work in concert with Rexin-G by providing a localized cancer vaccination aimed at gaining additional tumor control.

According to Dr. Erlinda M. Gordon, Medical Director of Epeius Biotech, “Based on the clear survival benefits of Rexin-G that we are seeing in our clinical trials, we felt obligated to advance this new product to provide an opportunity for personalized cancer vaccination in patients who may still be at risk for recurrence.”

Reximmune-C is a tumor-targeted gene delivery vector delivering an immune-stimulating cytokine gene directly to residual tumors, with the intent of generating a localized vaccination to encourage a lasting anti-tumor immunity. The IJO paper summarizes the preclinical studies, pilot clinical studies, and the elegant vector design engineering embodied in Reximmune-C, which make this clinical application possible.

About Epeius Biotechnologies

Epeius Biotechnologies Corporation is a privately held biopharmaceutical company dedicated to the advancement of genetic medicine with the development and commercialization of its proprietary targeted delivery systems. To learn more about our pipeline of proprietary biotechnologies currently available for clinical development and/or new product development, please visit us at www.epeiusbiotech.com.

For more information about Rexin-G, Reximmune-C, on-going clinical trials in the USA and abroad, and/or Epeius pathotropic (disease-seeking) gene delivery systems, please contact Dr. Erlinda M. Gordon at egordon@epeiusbiotech.com.

[tags]Epeius Biotechnologies, cancer vaccination in situ, medical gene delivery, International Journal of Oncology[/tags]

Cutting-Edge Cancer Research Threatened by Government Cutbacks

James Street — Wed, 10 Nov 2010 19:11:27 +0000

Friends of Susan, a 100% efficient nonprofit, funds innovative, focused cancer research; foundation’s goal is $1,000,000 by 2011

LOS ANGELES, Nov. 10, 2010 /PRNewswire-USNewswire/ — Friends of Susan, a new tax-exempt nonprofit organization, is dedicated to supporting cutting-edge medical research by funding internationally-renowned Dr. Thomas Kipps, who is convinced that understanding chronic lymphocytic leukemia (CLL) is key to curing breast, prostate and other cancers.

Every ten minutes in the United States, someone dies from a blood cancer; Susan Fine lost her battle with CLL in 2009. One of her last requests was that her family continue to fight cancer with a 100% efficient fundraising organization, which gave rise to Friends of Susan. Every dollar donated goes directly to support Dr. Kipps’ groundbreaking research. The foundation’s stated fundraising goal is $1,000,000 before the end of 2010, in order to keep pace with the achievements of prior years.

Recent cutbacks in federal funding for cancer research and a steady decline in the level of financial support from the business community have created the need for organizations like Friends of Susan to make broad appeals for donations in order to support a consistent level of innovation in research.

“The cure and control for breast and prostate cancer are directly linked to fully understanding the workings of the cells in a disease like CLL,” says Dr. Kipps. “I’m developing a method to deliver a specially modified gene directly into tumor cells in the patient. Once embedded, the gene would produce molecules designed to convert the tumor into a microscopic vaccine-manufacturing plant. In this way, cancer-killing vaccine would be produced internally over a period of time and would access… cancer cells that are not accessible to the surgeon.”

Kipps, Deputy Director of Research at the Moores UCSD Cancer Center and a Professor of Medicine at UC San Diego’s School of Medicine, is internationally recognized for his contributions to the understanding of the immunobiology, cell biology and molecular genetics of human B-cell malignancies, with emphasis on CLL. He is also the chairman of the CLL Research Consortium (CRC), which unites some of the nation’s top clinical and laboratory sites to avoid duplication of efforts and implement actual treatments and cures from lab bench research.

Donations to support Dr. Kipps’ research can be made via FriendsofSusan.org. For a limited time, Friends of Susan is pleased to offer donors a choice of “thank you” gifts with contributions.

For more information about the “thank you gift” program or Dr. Kipps and his work including videos and testimonials visit FriendsofSusan.org.

About Friends of Susan: Friends of Susan is a 501(c)(3) tax-exempt nonprofit organization of people who want to help fund life-saving cancer research that is threatened because of government cutbacks. These cutbacks reduce the availability of drugs and knowledge necessary to treat all types of cancer in their lifetime. Forcing them to wait patiently is the same as saying that there is little hope for them to conquer the diseases that are taking their lives away. Researchers agree that early detection of cancer is the key to controlling the growth of the disease. Determining the markers that will predict the type, growth rate and strength of all forms of cancer is the best strategy for patients and health care professionals as they decide on which treatments to use to battle this disease. Friends of Susan is funding cutting edge research to find those markers now. Learn more via FriendsofSusan.org, or connect with Friends of Susan via Facebook or Twitter.

SOURCE Friends of Susan

New protein found for cancer treatment

James Street — Sat, 06 Nov 2010 04:59:17 +0000

Friday, November 05, 2010 09:57 AM

Researchers at the University of Cambridge University have discovered a protein in cancer tumor that suppresses immunity, which could potentially help produce improved vaccine to fight the disease.

A type of stromal cell found in many cancers that expresses a protein called – fibroblast activation protein alpha (FAP), is the key to suppressing immune response in the cancer tumor.

The study, published in the journal Science, said that if these cells are destroyed, the immune system in an individual can be improved to fight cancer.

“Finding the specific cells within the complex mixture of the cancer stroma that prevents immune killing is an important step. Further studying how these cells exert their effects may contribute to improved immunological therapies by allowing us to remove a barrier that the cancer has constructed,” said Douglas Fearon, Sheila Joan Smith Professor of Immunology of the Department of Medicine at the University of Cambridge.

Most vaccines that build the immunity in the body to attack cancerous cells in tumors have never affected the growth of tumors. This finding could change the situation.

“These studies are in the mouse, and although there is much overlap between the mouse and human immune systems, we will not know the relevance of these findings in humans until we are able to interrupt the function of the tumor stromal cells expressing FAP in patients with cancer,” said Professor Fearon.

Mifamurtide in osteosarcoma–a practical review.

James Street — Tue, 28 Sep 2010 01:21:51 +0000

Anderson PM, Tomaras M, McConnell K.

University of Texas, MD Anderson Cancer Center, Dept. of Pediatrics, Houston, Texas 77030-4009, USA. pmanders@mdanderson.org
Abstract

Mifamurtide, also known as liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE), has been approved for the treatment of osteosarcoma in Europe. Mifamurtide’s rational drug design employs MTP-PE for macrophage activation in a multilamellar liposome drug carrier, containing the synthetic phospholipids 1-palmitoyl-2-oleoyl phosphatidyl choline (POPC) and 1,2-dioleoyl phosphatidyl serine (OOPS). Although the drug is not cytotoxic towards normal or tumor cells in vitro, immune activation against osteosarcoma lung metastases in vivo accounts for mifamurtide’s antiosteosarcoma effects. Phosphatidyl serine-containing lipids signal macrophage cells that have “flipped phosphatidyl serine” to the outer membrane after apoptosis (e.g., after damage of tumor cells from chemotherapy); thus, both mifamurtide’s active and inactive ingredients target immune cells in the lungs. Mifamurtide administration has resulted in 8% and 13% improvement in 6- and 5-year overall survivals, when added to chemotherapy in nonmetastatic and metastatic patients with osteosarcoma, respectively. The short-term toxicities of mifamurtide (fever, headache, flu-like symptoms and rigors) are reduced or eliminated using ibuprofen (200 mg) as premedication for the first infusion; an algorithm for pre- and postmedication is presented. To date, no long-term side effects of mifamurtide have been reported. Compassionate access programs based in two major cancer centers (MD Anderson and Memorial Sloan-Kettering), have recently provided this potentially life-saving drug in North America. The experience with mifamurtide provides an outstanding example of successful cooperation among regulatory bodies and agencies, the pharmaceutical industry and pediatric oncologists to improve cancer care and outcomes for children and young people with a rare sarcoma.

Vaccine May Block Tumor Growth in Some Cancers

James Street — Wed, 04 Aug 2010 06:00:37 +0000

Virus-based vaccine found to activate immune systems in some patients with advanced cancers

MONDAY, Aug. 2 (HealthDay News) — An experimental vaccine based on an encephalitis virus may be able to block tumor growth in some advanced cancers by stimulating an immune response — even when an immune system has been suppressed, according to a study published online Aug. 2 in the Journal of Clinical Investigation.

Michael A. Morse, M.D., of the Duke University Medical Center in Durham, N.C., and colleagues treated 28 patients with advanced cancer, or cancer that had been unresponsive to treatment, with a vaccine created by removing replication genes from the Venezuelan equine encephalitis virus (an alphavirus) and replacing them with genes for the production of carcinoembryonic antigen, found in cancer cells. Over three months, the patients received up to four vaccine injections plus booster shots.

The researchers found that the vaccine generated an immune response against the tumor cells in some patients. Two patients with no evidence of disease remained in remission, two patients maintained stable disease, and one patient with pancreatic cancer had a lesion on his liver disappear. The remaining patients did not respond to the therapy. Patients with the smallest amount of tumor appeared to benefit most from the therapy.

“These data suggest that virus-like replicon particle-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen, and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression,” the authors write.

Several study authors disclosed employee relationships with Alphavax.

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