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Attacking
cancer indirectly: Generating immunity against tumor vessel protein in mouse
study
Attacking
cancer indirectly: Generating immunity against tumor vessel protein in mouse
study
Date:
April 25,
2014
Source:
Perelman School of Medicine at the
University of Pennsylvania
Summary:
A novel DNA vaccine is being trialed to kill cancer,
not by attacking tumor cells, but targeting the blood vessels that keep them
alive. The vaccine also indirectly creates an immune response to the tumor
itself, amplifying the attack by a phenomenon called epitope spreading. The
team injected mice with a DNA fusion vaccine. In mouse models of three cancer
types, tumor formation was delayed or prevented in mice vaccinated with the
vaccine. Specifically, they found that the mouse tumors had suppressed growth,
decreased tumor vessel formation, and increased infiltration of immune cells
into tumors.
...........................
Sometimes a full-on assault isn't the best approach when
dealing with a powerful enemy. A more effective approach, in the long run, may
be to target the support system replenishing the supplies that keep your foe
strong and ready for battle. A group of researchers from the Abramson Cancer
Center and the Perelman School of Medicine at the University of Pennsylvania is
pursuing this strategy by employing a novel DNA vaccine to kill cancer, not by
attacking tumor cells, but targeting the blood vessels that keep them alive.
The vaccine also indirectly creates an immune response to the tumor itself,
amplifying the attack by a phenomenon called epitope spreading. The results of
the study were published this month in the Journal
of Clinical Investigation.
Previous
studies have targeted tumor angiogenesis (the formation of new blood vessels
that feed the tumor cells). However, this approach can also interfere with
normal processes involved in wound healing and development. Penn researchers
avoided this pitfall by designing a DNA vaccine that specifically targets TEM1
(tumor endothelial marker 1), a protein that is overexpressed in tumors and
poorly expressed in normal tissues.
"We
demonstrated that by targeting TEM1, our vaccine can decrease tumor
vascularization, increase hypoxia of the tumor and reduce tumor growth,"
says Andrea Facciabene, PhD, research assistant professor of Obstetrics and
Gynecology and a faculty member in the Ovarian Cancer Research Center at Penn
Medicine. "Our results confirm that we were directly targeting the tumor
vasculature and also indirectly killing tumor cells through epitope
spreading."
The Penn
team injected mice with a DNA fusion vaccine called TEM1-TT, created by fusing
TEM1 complementary DNA with a fragment of the tetanus toxoid (TT). In mouse
models of three cancer types (breast, colon, and cervical), tumor formation was
delayed or prevented in mice vaccinated with the TEM1-TT DNA vaccine.
Specifically, they found that the mouse tumors had suppressed growth, decreased
tumor vessel formation, and increased infiltration of immune cells into tumors.
The
researchers found that the DNA vaccine, after killing the endothelial cells
that make up the tumor vessels (vasculature), also resulted in epitope
spreading, meaning that the immune cells of the mice gathered pieces of dead
tumor cells (due to hypoxia) to create a secondary immune response against the
tumor itself. The vaccine induced specific T cells to fight other tumor cells
expression other proteins, in addition to TEM1, thus increasing its therapeutic
efficacy.
The new DNA
vaccine approach to fight cancer is showing great potential compared to
previous studies that focused on tumor cells rather than the blood vessels that
allow tumor cells to thrive.
"Until
now there have been a lot of clinical trials using DNA vaccines to target
tumors themselves, but unfortunately the results have been disappointing,"
Facciabene notes. "This is a different approach which should heighten
optimism for cancer vaccines in general. Moreover, based on what we've seen in
our mouse studies, this vaccine doesn't seem to show any significant side
effects."
The
prevalence of TEM1 in a wide range of tumor types coupled with its scarcity in
normal vessels makes it a suitable target both for a prophylactic defense
against cancer and a complement to other therapies such as radiotherapy and
chemotherapy. "Using this vaccine simultaneously with radiation may
eventually have a double synergy," Facciabene says. "Both treatments
affect the tumor endothelium, radiotherapy could help the phenomenon of epitope
spreading induced by the TEM1-TT vaccine." In addition to ongoing
pre-clinical work with human TEM1, Facciabene and colleagues are planning to
move on to Phase I human clinical trials.
The authors
suggest that TEM1 may also be an excellent target as a prophylactic cancer
vaccine for individuals that have a high risk of developing ovarian cancer,
such as carriers of the BRCA1/2 mutations, predominant in breast and ovarian
cancer. Research to develop those types of strategies is a key goal of Penn's
Basser Research Center for BRCA. As a bonafide vaccine, TEM-TT DNA vaccine
generates a memory immune response, which Facciabene says is an ideal attribute
for high risk populations.
Story
Source:
The above
story is based on materials provided by Perelman School of Medicine at the University of
Pennsylvania. Note: Materials may be edited for content and length.
Journal
Reference:
- John G. Facciponte, Stefano Ugel, Francesco De Sanctis, Chunsheng Li, Liping Wang, Gautham Nair, Sandy Sehgal, Arjun Raj, Efthymia Matthaiou, George Coukos, Andrea Facciabene. Tumor endothelial marker 1–specific DNA vaccination targets tumor vasculature. Journal of Clinical Investigation, 2014; 124 (4): 1497 DOI: 10.1172/JCI67382
Cite This
Page:
Perelman School of Medicine at the
University of Pennsylvania. "Attacking cancer indirectly: Generating
immunity against tumor vessel protein in mouse study." ScienceDaily.
ScienceDaily, 25 April 2014.
<www.sciencedaily.com/releases/2014/04/140425162148.htm>.
