Most ovarian cancer patients are diagnosed with late
stage disease that is unresponsive to existing
therapies. In a new study, researchers from the
Perelman School of Medicine at the University of
Pennsylvania School of Medicine show that a two-step
personalized immunotherapy treatment — a dendritic
cell vaccine using patients’ own tumor followed by
adoptive T cell therapy — triggers anti-tumor immune
responses in these type of patients. Four of the six
patients treated in the trial responded to the
therapy, the investigators report this month in
OncoImmunology.
"What we proved in this study is that this is a safe
treatment strategy," says co-first author Lana
Kandalaft, PharmD, MTR, PhD, research assistant
professor of Obstetrics and Gynecology and director
of clinical development in the Ovarian Cancer
Research Center. "It is a walk in the park for
patients, especially compared to standard
chemotherapies and surgical treatments for ovarian
cancer – literally, some patients left the clinic
and went for a walk in a nearby park after their
treatment."
The findings follow research by the study’s senior
author, George Coukos, MD, PhD, director of the
Ovarian Cancer Research Center at Penn, who showed
in 2003 that women whose ovarian tumors were
infiltrated by healthy immune cells, called T cells,
tended to live longer than women whose tumors were
devoid of T cells.
That observation and other subsequent ones suggest
the patient's immune system is trying to fight off
the disease but can't quite muster the strength to
beat it. Therefore, investigators have been trying
to find ways using patients’ own tumor cells to
boost the immune system's power.
In the current study, Coukos, Kandalaft, co-first
author Daniel J. Powell Jr., PhD, research assistant
professor of Pathology and Laboratory Medicine, and
colleagues treated six women with advanced ovarian
cancer in a two-staged immunotherapy protocol in
which they utilized a dendritic cell vaccine created
from tissue in the patients’ own tumor, which was
stored at time of surgery. All of these women’s
cancers had progressed on standard of care
chemotherapy.
In the first segment of the study, the team prepared
an individualized dendritic cell vaccine for each
patient. They harvested dendritic cells from each
patient using apheresis, the same process volunteers
go through when they donate platelets or other blood
products such as those collected for stem cell
transplants. Kandalaft and colleagues then exposed
each patient's dendritic cells to tumor extract
produced from the woman's own tumor, which teaches
the dendritic cells who the enemy is. After this
priming, the investigators vaccinated each patient
with her own dendritic cells and gave them a
combination chemotherapy regimen of bevacizumab and
cyclophosphamide. Because dendritic cells are like
the generals of the immune system, they then induce
other immune cells to take up the fight.
Of the six patients who received the dendritic cell
vaccine, four developed an anti-tumor immune
response, indicating that the approach was working.
One of those patients had no measurable disease at
study entry because all of it had been successfully
removed during surgery. She remains in remission
today, 42 months following vaccine treatment. The
other three who had an immune response to the
vaccine still had residual disease and went on to
the second segment of treatment.
The team harvested T cells from each of these three
women. Using a technique developed at Penn, they
grew the cells in the laboratory, expanding their
numbers exponentially, and then reintroduced them
into each patient after she underwent a
lymphodepleting chemotherapy regimen. Because the T
cells had already been trained by the dendritic cell
vaccine to attack the tumor cells, the adoptive T
cell transfer amplifies the anti-tumor immune
response.
Two of the women showed a restored immune response
after the T cell transfer. One of the women
continued to have stable disease, whereas the other
had a complete response to the therapy.
The researchers say it is too early to say whether
this type of therapy will be effective in a large
number of ovarian cancer patients, but the early
results are promising. First, and foremost, she
notes, the two-step approach appears safe and well
tolerated by the patients. Additionally, the team
saw a correlation in both treatment steps between
immune responses and clinical benefit, suggesting
that it is, in fact, the immune response that is
holding the disease in check.
With these encouraging results in hand, the team has
opened a larger trial in which they have already
enrolled about 25 women and aim for up to 30 more.
The new protocol uses an improved vaccine platform
and an optimized adoptive T cell transfer protocol.
The PI of this study is Janos Tanyi, MD, PhD.
“Large clinical trials have shown that intensifying
chemotherapy doesn't improve outcomes for women with
advanced ovarian cancer,” Coukos says. “So we need
to explore other avenues. We think the combinatorial
approach of both immune and chemotherapy is the way
to go.”
Other co-authors from Penn include Cheryl L. Chiang,
Janos Tanyi, Sarah Kim, Kathy Montone, Rosemarie
Mick, Bruce L. Levine, Drew A. Torigian, and Carl H.
June. Co-author Marnix Bosch is from Northwest
Biotherapeutics in Bethesda, MD.
This study was supported by National Cancer
Institute Ovarian SPORE grant P01-CA83638, National
Institution of Health R01FD003520-02, and the
Ovarian Cancer Immunotherapy Initiative.
For more information
Lana E. Kandalaft, Daniel J. Powell Jr., Cheryl L.
Chiang, Janos Tanyi, Sarah Kim, Marnix Bosch, Kathy
Montone, Rosemarie Mick, Bruce L. Levine, Drew A.
Torigian, Carl H. June and George Coukos.
Autologous lysate-pulsed dendritic cell vaccination
followed by adoptive transfer of vaccine-primed ex
vivo co-stimulated T cells in recurrent ovarian
cancer
http://www.landesbioscience.com/journals/oncoimmunology/2012ONCOIMM0295R.pdf
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