Vaccine Against Prostate Cancer Activates "Entire Immune System," Johns
Hopkins Team Says

20-Oct-1999 - Johns Hopkins cancer researchers report the successful use
of human gene therapy to activate the human immune system against
metastatic prostate cancer. The achievement could have implications in
the treatment of many kinds of cancer. The study results are published
in the October 15, 1999 issue of Cancer Research.
The Hopkins team injected a genetically engineered cancer vaccine in 11
prostate cancer patients whose cancer continued to spread following
total surgical removal of their prostate glands. "We were astounded to
find that every part of the immune system was alerted and turned on,"
says Jonathan Simons, M.D., associate professor of oncology and urology
and principal investigator of this study, funded by the CaP Cure
Foundation, the National Cancer Institute, and the Department of Defense
Prostate Cancer Initiative.
"Using gene therapy, we re-educated the immune system to recognize
prostate cancer cells as a potential infection and attack," he says. To
create the vaccine, the researchers used cancer cells removed from the
patient's own prostate tumor during surgery and grew them in the
laboratory. GM-CSF, the most potent gene known to activate the immune
system to recognize tumor antigens, was inserted into the cancer vaccine
cells. The GM-CSF gene transfer into the cells was accomplished via a
retrovirus, itself genetically engineered to be safe in humans. The
GM-CSF gene-engineered prostate cancer vaccine was then irradiated to
prevent the cancer cells from growing and injected into the patient's
thigh like a flu shot.
Within four weeks of vaccination, the researchers were able to detect
circulation of immune cells throughout the bloodstream. Patients'
B-cells produced antibodies against prostate cells, and their T-cells
directly attacked the tumor, the researchers report. Once re-educated to
see prostate cells as foreign bodies, antigens on the cells' surface
serve as red flags to the immune system, causing it to seek out and
destroy them.
"The gene we used to turn on the immune system is so good that it
activates everything," says William G. Nelson, M.D., Ph.D. "We were not
surprised to see T-cell activation, the arm of the immune system
triggered by viruses, but this vaccine also stimulated new high-level
antibody production. Such a complete and thorough activation of the
immune system against prostate cancer has never before been seen," he
says.
All prostate cells are targets for this type of gene therapy because any
prostate cell that survives surgery has the potential to turn malignant
and become lethal to the patient. However, since the prostate is not a
vital organ, the researchers say destruction of the prostate cells is
safe and should not lead to incontinence or impotency as other therapies
sometimes can. In fact, the therapy is so well tolerated by patients
that no hospitalization is required. The only side effects associated
with this therapy are flulike symptoms and redness and itchiness at the
vaccine site for several days.
"The idea of using the immune system against prostate cancer is quite
novel, but offers real hope because many of our conventional treatments
do not kill metastatic cells efficiently," says Simons. "Genetically
engineered vaccines like this could make a real difference when used as
adjuvant therapy to 'mop up' microscopic cancer cells left behind
following surgery, chemotherapy, and radiation therapy," he continues.
"The ability to activate the immune system to produce antibodies against
cancer provides critical new fundamental information that will broaden
the potential of these gene therapy trials," Simons notes. Based on the
research reported in Cancer Research, Simons, Nelson, and team currently
are conducting larger trials using a genetically engineered prostate
cancer vaccine that does not require surgery. Advanced prostate cancer
patients can obtain information about these trials by calling (410)
614-4234.
Prostate cancer is the most common malignancy, striking more than
330,000 men in the United States each year. New therapies are urgently
needed for the approximately 40,000 men who die each year because their
cancer has spread beyond the prostate to the bone marrow and other vital
tissues and organs.
In addition to Simons and Nelson, other participants in this study
included Bahar Mikhak, Ju-Fay Chang, Angelo M. DeMarzo, Michael A.
Carducci, Michael Lim, Christine E. Weber, Angelo A. Baccala, Marti A.
Goemann, Shirley M. Clift, Dale G. Ando, Hyam J. Levitsky, Lawrence K.
Cohen, Martin G. Sanda, Richard C. Mulligan, Alan W. Partin, H.
Ballentine Carter, Steven Piantadosi, and Fray F. Marshall.
Related Web Sites and Stories
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Read the abstract of the published article on PuBMed:
Cancer Res 1999 Oct 15;59(20):5160-8 Induction of immunity to prostate
cancer antigens: results of a clinical trial of vaccination with
irradiated autologous prostate tumor cells engineered to secrete
granulocyte-macrophage colony-stimulating factor using ex vivo gene
transfer. Simons JW, et al Johns, Hopkins Oncology Center, Brady
Urological Institute, and Johns Hopkins University School of Medicine,
Baltimore, Maryland  http://www.med.jhu.edu/cancerctr/  
Therapeutic vaccines: Uncovering cancer's camouflage (American Medical
News) Despite past disappointments and some skepticism, scientists hope
they can induce an immunologic response to cancer with a therapeutic
vaccine.


knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."

Clinical Trials/ Immune Therapy
Vaccine Tf, Tn Now Testing on Prostate Cancer Patients at MSK

A new vaccine for prostate cancer, created by chemists at the
Sloan-Kettering Institute for Cancer Research, is being given to
patients who have undergone prostate cancer surgery. The aim is to ward
off a recurrence.
     Now in early trials with patients, this is the first
synthetic vaccine to target what the researchers describe as "abundant,
but elusive, carbohydrates on the surface of tumor cells."
     Using vaccines to stimulate an immune response against
cancer typically focuses on proteins. These are relatively easy to make
but often lodged within cells and not easy for antibodies to reach. Most
of the good targets, or antigens, on a cancer cell's surface are not
proteins, however. Instead they are small carbohydrates. But these small
carbohydrates are hard to make, and their role in giving rise to an
immune response is not well-understood.
     "Normally the carbohydrates are much more complex in normal
cells. In cancer cells they're often very different," says
Sloan-Kettering chemist Scott D. Kuduk, Ph.D. The difference may enable
scientists to target cancer.
     Kuduk's team synthesized two key tumor carbohydrate
antigens — called TF and Tn. They then clustered the antigens as they
occur naturally and attached them to proteins which help produce an
immune response.
     "Through chemistry, we were able to make substantial
quantities of the material that allowed us to then do the testing," adds
Kuduk. In mice, the Tn-protein complex was especially effective at
triggering antibody production.
     "It's a wonderful antigen for prostate cancer because Tn is
one of the main antigens on prostate cancer cells," says immunologist
and co-author Philip O. Livingston, M.D., who calls the advance "more
promising than other approaches."
    Although the vaccine is already being given to patients, the
researchers say it is too early to know whether a series of vaccinations
will provide an adequate defense against recurrence. Patients are
definitely producing antibodies against Tn, Livingstone says.
    Scientists hope the vaccines will specifically attack
prostate cancer cells, permanently curbing the cancer without side
effects.

knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."

 
Failure of cancer vaccines: the significant limitations of this approach
to immunotherapy.
Bodey B, Bodey B Jr, Siegel SE, Kaiser HE.

Department of Pathology, University of Southern California, Los Angeles
91335, USA. Bodey18@aol.com

Immunotherapy has always represented a very attractive fourth-modality
therapeutic approach, especially in light of the many shortcomings of
conventional surgery, radiation, and chemotherapies in the management of
cancer. Subsets of neoplastically transformed cells have been shown to
(re-)express on their surface molecules which are not typically present
on the surface of neighboring normal cells. In some instances,
especially in malignant melanomas, cytotoxic T lymphocytes (CTLs)
directed against such tumor associated antigens (TAAs) have been
isolated. The cancer vaccine approach to therapy is based on the notion
that the immune system could possibly mount a rejection strength
response against the neoplastically transformed cell conglomerate.
However, due to the low immunogenicity of TAAs, downregulation of MHC
molecules, the lack of adequate costimulatory molecule expression,
secretion of immunoinhibitory cytokines, etc., such expectations are
rarely fulfilled. Various approaches have been explored ranging from the
use of irradiation inactivated whole-cell vaccines derived from both
autologous and allogeneic tumors (even tumor cell lines), and
genetically modified versions of such cellular vaccines which aim at
correcting costimulatory dysfunction or altering the in situ humoral
milieu to aid immune recognition and activation. Anti-idiotype vaccines,
based on cancer cell associated idiotypes, have also been explored which
aim at increasing immunogenicity through in vivo generation of vigorous
immune responses. Dendritic cell (DC) vaccines seek to improve the
presentation of TAAs to naive T lymphocytes. Unfortunately, there is
always the possibility of faulty antigen presentation which could result
in tolerance induction to the antigens contained within the vaccine, and
subsequent rapid tumor progression. The theoretical basis for all of
these approaches is very well founded. Animal models, albeit highly
artificial, have yielded promising results. Clinical trials in humans,
however, have been somewhat disappointing. Although general immune
activation directed against the target antigens contained within the
cancer vaccine has been documented in most cases, reduction in tumor
load has not been frequently observed, and tumor progression and
metastasis usually ensue, possibly following a slightly extended period
of remission. The failure of cancer vaccines to fulfill their promise is
due to the very relationship between host and tumor: through a natural
selection process the host leads to the selective enrichment of clones
of highly aggressive neoplastically transformed cells, which apparently
are so dedifferentiated that they no longer express cancer cell specific
molecules. Specific activation of the immune system in such cases only
leads to lysis of the remaining cells expressing the particular TAAs in
the context of the particular human leukocyte antigen (HLA) subclass and
the necessary costimulatory molecules. The most dangerous clones of
tumor cells however lack these features and thus the cancer vaccine is
of little use. The use of cancer vaccines seems, at present, destined to
remain limited to their employment as adjuvants to both traditional
therapies and in the management of minimal residual disease following
surgical resection of the primary cancer mass.
Publication Types:
Review
Review, Tutorial
PMID: 10953341 [PubMed - indexed for MEDLINE]

Aug 30 2004 06:52:01
 

knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."

August 31, 2000, New York -- Results from preliminary laboratory studies
provide the first functional evidence that developing a "universal"
cancer vaccine might be possible, researchers from Duke University
Medical Center and Geron Corp. reported Tuesday.
The scientists found that the active part of telomerase, a protein
expressed in all major human cancers, can stimulate development of
immune cells when used as the basis for a cancer vaccine. Furthermore,
these immune cells can kill multiple, unrelated mouse and human cancer
cells in the test tube and can also slow tumor growth in mice.
While not as effective as vaccines based on a tumor's entire genetic
material, the promising results of these early studies indicate the
potential of this telomerase-based vaccine as one component of a
"universal" cancer vaccine, the researchers said in reporting their
findings in the Sept. 1 issue of the journal Nature Medicine.
Cancer vaccines are being tested to help the body fight off certain
existing cancers or to keep a cancer from returning, rather than to
prevent the disease from developing initially. Like vaccines that
prevent other diseases, cancer vaccines work by stimulating the immune
system to build an army of cells that recognize, attack and kill the
target cells -- in this case, cancer cells.
"The question posed in the study was whether the telomerase-based
vaccine can stimulate an immune response from cancer patients, and
whether those cells can attack and kill the patient's tumor cells,"
explained Eli Gilboa, principal investigator of the study and director
of the Center for Genetic and Cellular Therapies at Duke. "The results
of this study are the first indication that a more broadly applicable
cancer vaccine might be possible."
Most known tumor-specific antigens -- proteins displayed on tumor cells
but not normal cells -- are primarily associated with a single cancer
type, such as prostate specific antigen (PSA). Even CEA, or
carcinoembryonic antigen, which is found in 90 percent of colon cancers,
40 percent of breast cancers, and to lesser degrees in other cancers,
can't match the broad expression of telomerase in human cancer,
scientists said.
"The thinking has been that because every cancer is different --
melanoma, breast, etc. -- that each cancer has its own specific set of
antigens that must be used for a vaccine," said Gilboa, who is also
professor of experimental surgery and member of the Duke Comprehensive
Cancer Center. "We're looking for a universal antigen -- one antigen to
try to treat every cancer patient." Because telomerase is found in some
types of normal cells, the scientists weren't sure an immune response
against it would even be possible, Gilboa said. Telomerase rebuilds the
repetitive ends of chromosomes, called telomeres, one step in many that
allow cancer cells to divide unchecked. In normal cells that lack
telomerase, the telomeres become shorter each time the cell's DNA is
copied. Geron has many patents and pending applications related to
telomerase, including its use as an antigen for cancer therapy.
"In spite of the fact that telomerase is a self-antigen, the body has
not developed a complete tolerance to it and we were able to stimulate
an immune response against it," Gilboa said. "However, by itself,
telomerase is not a strong antigen, so to make an effective, broadly
applicable cancer vaccine we will need to optimize and possibly combine
it with other universal antigens." Using techniques developed in
Gilboa's lab, the researchers used RNA, the instructions for building
proteins, to teach so-called dendritic cells to make a certain part of
the telomerase protein, called TERT, and display it on their surface.
Dendritic cells act as most-wanted posters for the immune system,
showing immune cells how to recognize foreign cells and stimulating
development of immune cells called cytotoxic T lymphocytes -- killer T
cells -- that look specifically for cells matching the dendritic cells'
display.
The scientists also made tumor-specific vaccines by using all of a tumor
cell's RNA and compared its effectiveness to the TERT vaccine. While the
tumor-RNA vaccines stimulated immune responses that more efficiently
killed tumor cells, the telomerase-based vaccine stimulated an immune
response that recognized and killed a much wider variety of cancer
cells. The TERT vaccine stimulated an immune response that slowed tumor
growth of melanoma, breast and bladder cancers implanted into
genetically unrelated mice, and an effective response against two
different mouse cancer cell lines in lab studies. No other vaccine was
able to induce such a broad immune response.
Besides testing the TERT vaccine in mice, researchers led by Dr.
Johannes Vieweg, a co-principal investigator of the study and assistant
professor of urology at Duke, obtained cells from human cancer patients
to see if an immune response against TERT could be developed. They used
tumor cell RNA to create a tumor-specific vaccine from each patient, and
each vaccine stimulated formation of tumor-specific killer T cells when
incubated with blood cells from the patient, they reported. In addition,
the TERT vaccine stimulated development of TERT-specific immune cells
from each patient's cells.
Because it is difficult to obtain enough tumor cells from most patients
to test immune cells' activity directly, the researchers used the
tumor-RNA vaccine cells in place of tumor cells. Theoretically, the
dendritic cells in the vaccine display all of the tumor's proteins,
Vieweg noted.
In laboratory experiments, the tumor vaccine-stimulated immune cells and
TERT-stimulated immune cells from each patient were able to recognize
and kill the patient's tumor-RNA vaccine cells. Furthermore, for the one
patient whose kidney cancer was established as a cell line, the immune
cells were able to recognize and kill the patient's tumor cells in test
tubes in addition to the patient's vaccine cells, validating the use of
the vaccine as a surrogate for tumor cells. No longer is it necessary to
have a large supply of tumor cells to verify immune activity, Vieweg
said.
"By using dendritic cells transfected with tumor RNA -- the
tumor-specific vaccine itself -- as a surrogate for human tumor cells in
laboratory studies, we can expand the scope of antigen discovery and
validation," Gilboa said. "It's not perfect, of course, because the
vaccine cells may display the antigens differently than the cancer cell
would, but it is a very useful screening method for identifying broadly
expressed human cancer antigens needed for a universal cancer vaccine."
The study was funded by an anonymous gift to the Duke Comprehensive
Cancer Center. Co-authors on the study are Smita Nair, Axel Heiser,
David Boczkowski and Michio Naoe of Duke, and Anish Majumdar and Jane
Lebkowski of Geron Corp., Menlo Park, Calif.
Duke University


knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."

This study is no longer recruiting patients.

Sponsored by
National Cancer Institute (NCI)

Purpose

This study will compare the effectiveness of the drug nilutamide with
that of an experimental vaccine in controlling advanced prostate cancer.
Nilutamide (Nilandron) is an anti-androgen approved for treating
prostate cancer. The vaccine is composed of the following parts: rV-PSA
- vaccinia virus plus human DNA that produces PSA (prostate specific
antigen); rV-B7.1 - vaccinia virus plus human DNA that produces B7.1 (a
protein that helps guide immune cells to their targets); rF-PSA -
fowlpox virus plus human DNA that produces PSA; and GM-CSF and IL-2 -
drugs that boost the immune system.

Patients 18 years or older who have advanced prostate cancer that has
not responded to hormonal therapy and who have been vaccinated against
smallpox may be eligible for this study. Patients must have a rising PSA
level but no X-ray evidence of tumor spread to other parts of the body.
Candidates will be screened with X-rays, CT and MRI scans, skin tests
similar to those for allergy or tuberculosis testing, and blood tests.
Participants will be randomly assigned to one of the following treatment
groups:

1. Vaccination - Patients in this group will receive the vaccine in
28-day treatment cycles, delivered in five parts during each cycle, as
follows: GM-CSF on days 1 through 4; IL-2 days 8 through 12; rV-PSA and
rV-B7.1 day 2; and rF-PSA days 30, 58, 86, etc. (i.e., every 4 weeks,
beginning 4 weeks after the first rV-PSA and rV-B7.1 injection). The
vaccinations are injected under the skin of the upper arm. Treatment
will continue as long as the cancer is controlled and there are no
serious side effects. Patients will have 15 cc (one tablespoon) of blood
drawn once a week for the first month and then 60 cc (4 tablespoons)
once every 4 weeks. Scans and X-rays will be done after 3 months, 6
months, and then every 2 months. Patients who, after 6 months, have a
rising PSA level but no X-ray evidence of disease progression will be
offered the option of switching to nilutamide therapy.

2. Nilutamide - Patients in this group will take the hormone by mouth, 6
tablets per day for the first month and 3 tablets per day thereafter.
Treatment will continue as long as the cancer is controlled and there
are no serious side effects. Patients will have 15 cc (one tablespoon)
of blood drawn once a week for the first month and then 60 cc (4
tablespoons) once every 4 weeks. Patients who, after 6 months, have a
rising PSA level but no X-ray evidence of disease progression will be
offered the option of switching to vaccine therapy.

All patients will have HLA tissue typing at the beginning of the study.
Those who are type HLA-A2 will be asked to undergo the following
additional procedures, which enable studies of the immune response that
can be done only with this tissue type.

- Lymphapheresis - A procedure similar to donating whole blood, but
requiring 2 to 3 hours. In lymphapheresis, the blood is separated into
its components by a machine, the lymphocytes (a type of white blood
cell) are removed, and the rest of the blood is returned to the body.

- Blood collection (60 cc) every 4 weeks

- Prostate biopsy - Removal of a small sample of tumor tissue, done
under local anesthetic.
Condition Treatment or InterventionPhaseProstate Cancer
Prostate Neoplasm
 Drug: rV-PSA
 Drug: rF-PSA
 Drug: rV-B7.1
Phase II
MedlinePlus related topics:  Prostate Cancer
Study Type: Interventional

Study Design: Treatment, Safety/Efficacy
Official Title: A Randomized Phase II Study of Either Immunotherapy
w/a Regimen of Recombinant Pox Viruses that Express PSA/B7.1 + Adjuvant
GM-CSF & IL-2 or Hormone Tx with Nilutamide in Patients w/Hormone
Refractory Prostate Ca and No Radiographic Evidence of Disease
Further Study Details: 
This trial will evaluate the efficacy and immunologic effects of a
vaccination regimen composed of (1) recombinant vaccinia virus that
expresses the Prostate Specific Antigen gene (rV-PSA) admixture, (2)
recombinant vaccinia virus that expresses B7.1 costimulatory admixture
(rV-B7.1), and (3) sequential vaccinations with recombinant fowlpox
virus containing the PSA gene (rF-PSA) compared to the efficacy of
antiandrogen therapy with Nilutamide in patients with hormone refractory
prostate cancer with increasing PSA levels but with no radiographic
evidence of metastatic disease. Patients randomized to the vaccine arm
will in addition receive GM-CSF and IL-2 as part of their vaccination
schedule. Patients will continue therapy monthly until there is
radiographic evidence of metastatic disease. Patients without disease
progression after 12 cycles, will receive the vaccine regimen every 12
weeks, until there is radiographic evidence of metastatic disease. The
primary endpoint is to identify progression of disease at six months to
determine if there is a statistically significant difference in time to
progression. At any interval at or after this 6 month time point,
patients with a rising PSA without radiographic evidence of disease
progression, will be offered the option to begin therapy with the
treatment offered in the other arm in addition to the treatment to which
they were randomized. Serum Immunologic markers and PSA levels will be
followed as secondary endpoints while patients continue to receive
treatment on the protocol. Patients with PSA-expressing adenocarcinoma
of the prostate will be evaluated for eligibility that includes a
history of prior vaccinia (as vaccine against smallpox) and
immunocompetence.
Eligibility
Genders Eligible for Study:  Male
Criteria

INCLUSION CRITERIA:
Patients with histologically confirmed diagnosis of adenocarcinoma of
the prostate without evidence of metastatic disease on scans, who are
hormone resistant with a rising PSA level. Hormone resistance is defined
as a rising PSA S/P orchiectomy and /or while receiving at least one
regimen of LHRH. Patients on antiandrogen therapy must undergo
antiandrogen withdrawal for at least one month and still evidence a
rising PSA. Following treatment with bicalutamide, patients must undergo
withdrawal for at least 6 weeks and still evidence a rising PSA.
Patients should have a serum PSA which has risen at least 0.5 ng/ml from
a baseline on 2 successive evaluations, each at least 1 week apart,
during and/or after treatment with hormonal therapy. Patients should
have an absolute minimal PSA level greater than 1.0 ng/ml.
Patients must have a bone scan and CT (or MRI) of the abdomen and pelvis
and chest CT or x-ray that shows no evidence of metastatic disease. The
scans must be completed within 6 weeks prior to the date of
randomization. Prostascint or similar immune-labeled scans will not be
considered to include or exclude evidence for metastatic disease.
Prior to randomization, patients will undergo HLA typing and will be
stratified as either HLA-A2 positive or HLA-A2 negative.

All HLA-A2 patients randomized to the vaccine arm who have not undergone
a prostatectomy will be encouraged to undergo U/S guided core biopsy of
their prostate gland at the NIH Clinical Center within 8 weeks prior to
beginning their vaccine therapy.

All HLA-A2 patients who have undergone a prostate biopsy will be
encouraged to undergo leukaphereses within 3 weeks prior to receiving
their first vaccination. These patients will also be encouraged to
undergo leukaphereses prior to their next two vaccinations.

Zubrod (ECOG) performance must be 0-2.
Age greater than or equal to 18 years.
At least 4 weeks must have elapsed since the last prior radiation
therapy, surgery, and/or hormonal therapy, at least 6 weeks must have
elapsed since the last dose of bicalutamide, and the patient must be
recovered from all acute toxicities of that therapy. No concurrent
chemotherapy, biologic therapy, or homeopathic therapy with PC-SPES or
genestein is permitted. Patients who progressed on LHRH agents must
remain on that agent or undergo surgical castration. Patients who have
not undergone orchiectomy must have a testosterone level drawn prior to
treatment and the result must be less than or equal to 50 ng/ml.

Patients must have received prior vaccinia (for smallpox immunization).
For all patients, recollection and appropriate vaccination-site scar is
sufficient evidence; otherwise, a physician certification of prior
smallpox immunization will suffice. Detectable anti-vaccinia antibodies
will serve as sufficient proof of prior vaccination for patients of any
age. Screening for anti-vaccinia antibodies will be performed only in
patients who don't meet the above criteria. There must be no history of
allergy or untoward reaction to prior vaccination with vaccinia virus.

Absolute lymphocyte count greater than or equal to 600/mm(3); platelets
greater than or equal to 100,000/mm(3); hemoglobin greater than or equal
to 8.0 grams/dl.
Serum bilirubin less than or equal to 1.6 mg/dl, AST and ALT less than
or equal to 4 times normal.
The initial urine analysis for eligibility should be grade less than or
equal to proteinuria, Grade 0 proteinuria, grade 0 hematuria, and no
abnormal sediment. Serum creatinine less than or equal to 1.5mg/dl or a
creatinine clearance greater than 60 ml/min. Patients may be eligible if
the underlying cause of the abnormality is determined to be non-renal.
Immunologic testing must be performed looking for a positive delayed
type hypersensitivity skin testing (e.g., to mumps, candida,
trichophyton and/or similar antigens). However, for patients with good
performance status, there is little correlation between skin test
response and the ability to respond to vaccine, thus a patient does not
need a positive test to be eligible for enrollment on this protocol.

Patients must understand and sign informed consent that explains the
neoplastic nature of his disease.

EXCLUSION CRITERIA:
Patients should have no evidence of being immunocompromised as defined
below:
Due to impaired cellular immunity, HIV patients are at an increased risk
of serious side effects from vaccinations with infectious agents;
Other diagnosis of altered immune function, or autoimmune disease
(autoimmune neutropenia, thrombocytopenia, or hemolytic anemia; systemic
lupus erythematous, Sjogren syndrome, or scleroderma; myasthenia gravis;
Goodpasture syndrome; Addison's disease, Hashimoto's thyroiditis, or
active Graves' disease);
Prior radiation therapy to greater than 50% of nodal groups;
Prior splenectomy;
Concurrent steroid use, except topical and inhaled steroids.
The recombinant vaccinia vaccine should not be administered if the
following apply to either recipients or, for at least two weeks after
vaccination, their close household contacts: persons with active or a
history of eczema or other eczematoid skin disorders; those with other
acute, chronic or exfoliative skin conditions (e.g. atopic dermatitis,
burns, impetigo, varicella zoster, severe acne or other open rashes or
wounds) until condition resolves; pregnant or nursing women; children
under 5 years of age; and immunodeficient or immunosuppressed persons
(by disease or therapy), including HIV infection. Close household
contact are those who share housing or have close physical contact.
Other serious intercurrent illness. Patients with active infections are
not eligible until the infection has cleared for at least three days.

History of other malignant process (excluding squamous cell or basal
cell carcinoma of the skin), unless that previous tumor was treated with
curative intent and the patient has been in remission for at least three
years. Patients with active or a history of CNS metastases are
ineligible.
Patients with a history of seizures, encephalitis, or multiple sclerosis
are not eligible.
Patients must not have a known allergy to eggs are not eligible.
Expected Total Enrollment:  78
Location Information
Maryland
      National Cancer Institute (NCI), 9000 Rockville
Pike,  Bethesda,  Maryland,  20892,  United States
More Information
Detailed Web Page
Publications
Townsend SE, Allison JP. Tumor rejection after direct costimulation of
CD8+ T cells by B7-transfected melanoma cells. Science. 1993 Jan
15;259(5093):368-70.
Chen L, Ashe S, Brady WA, Hellstrom I, Hellstrom KE, Ledbetter JA,
McGowan P, Linsley PS. Costimulation of antitumor immunity by the B7
counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell.
1992 Dec 24;71(7):1093-102.
Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ,
Armitage GR, Wilson JJ, Venner PM, Coppin CM, Murphy KC. Chemotherapy
with mitoxantrone plus prednisone or prednisone alone for symptomatic
hormone-resistant prostate cancer: a Canadian randomized trial with
palliative end points. J Clin Oncol. 1996 Jun;14(6):1756-64.
Study ID Numbers  000137;  00-C-0137
Study Start Date May 25, 2000
Record last reviewed  May 1, 2004
Last Updated  May 1, 2004
ClinicalTrials.gov Identifier  NCT00005759
ClinicalTrials.gov processed this record on 2004-09-03
U.S. National Library of Medicine, Contact NLM Customer ServiceNational
Institutes of Health, Department of Health & Human ServicesCopyright,
Privacy, Accessibility, Freedom of Information Act

knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."

This study is currently recruiting patients.

Sponsored by
National Cancer Institute (NCI)
Purpose
This study will test the ability of an experimental vaccine to prevent
the spread of localized prostate cancer following radiation therapy. The
vaccine is intended to stimulate immune cells called lymphocytes to
target and attack cells containing a protein called prostate specific
antigen, or PSA. It is composed of the following five parts: rV-PSA -
vaccinia virus plus human DNA that produces PSA (prostate specific
antigen); rV-B7.1 - vaccinia virus plus human DNA that produces B7.1 (a
protein that helps activate immune cells); rF-PSA - fowlpox virus plus
human DNA that produces PSA; and GM-CSF and IL-2 - two drugs that boost
the immune system.
Patients age 18 years and older with prostate cancer confined to the
prostate who have been vaccinated against smallpox (vaccinia virus
vaccine) and who do not have a history of allergy to eggs may
participate in this study. Candidates will be screened for eligibility
with a complete medical history and physical examination, skin tests
(similar to those for allergies or tuberculosis) to assess immune
function and blood tests.
Participants will be randomly assigned to one of two treatment groups:
one will receive standard radiation therapy, but no vaccine; the other
will receive standard radiation therapy plus the experimental vaccine.
Patients in both groups may receive hormone therapy, if indicated.
Patients in the vaccine group will receive up to eight vaccinations in
28-day treatment cycles, as follows: GM-CSF on days 1 through 4; IL-2
days 8 through 12; rV-PSA and rV-B7.1 day 2 of the first cycle only; and
rF-PSA (booster shots) every 28 days, beginning day 2 of the second
cycle (i.e., days 30, 58, 86, etc.). The vaccinations are injected under
the skin of the upper arm. Treatment will continue for eight cycles
unless serious side effects develop, PSA levels rise significantly, or
the doctors feel there is no reason to continue. Radiation therapy will
be started about 3 months after enrollment in the study. Patients will
have 15 cc (one tablespoon) of blood drawn once a week for the first
month and then 60 cc (4 tablespoons) once every 4 weeks. After treatment
ends, patients will have follow-up examinations and blood tests every 3
months for the first 2 years and then every 6 months until the doctors
determine follow-up is no longer needed or the cancer returns.
All patients will have HLA tissue typing at the beginning of the study.
Only those who are HLA-A2 positive can go on this study. This will
enable studies of the immune response that can be done only with this
tissue type. These include blood collection (60 cc) every 4 weeks and a
procedure called lymphapheresis for collecting white blood cells. In
this procedure, whole blood is collected through a needle in an arm
vein, similar to donating a unit of blood. The blood flows through a
machine that separates it into its components. The white cells are
removed, and the red cells, platelets and plasma are returned to the
body, either through the same needle used to draw the blood or through a
second needle in the other arm.
Condition Treatment or InterventionPhaseProstate Cancer
Prostate Neoplasm
 Drug: rV-PSA
 Drug: rF-PSA
 Drug: rV-B7.1
Phase II
MedlinePlus related topics:  Prostate Cancer
Study Type: Interventional
Study Design: Treatment, Safety/Efficacy
Official Title: A Randomized Phase II Study of a PSA-Based Vaccine in
Patients with Localized Prostate Cancer Receiving Standard Radiotherapy
Further Study Details: 
This trial will evaluate the immunologic effects of a vaccination
regimen in HLA-A2 positive prostate cancer patients. Eligible patients
will have localized prostate cancer and be willing to undergo definitive
local radiotherapy. 30 patients will be randomized in a 2:1 ratio into
two cohorts (see schema below) with patients in the vaccine arm
receiving vaccination before, during and after primary standard
radiotherapy (external beam alone or in combination with brachytherapy).
When enrollment to these two cohorts is complete, enrollment will begin
with up to 19 (9-10 HLA-A2 positive) patients to a third, non-randomized
vaccine cohort. This cohort C will differ from the first vaccine cohort
only in the IL-2 dose and schedule. The vaccine regimen will be composed
of (1) a recombinant vaccinia virus that expresses the Prostate Specific
Antigen gene (rV-PSA), admixed with (2) a recombinant vaccinia virus
that expresses B7.1 costimulatory molecule (rV-B7.1); followed by (3)
sequential vaccinations with recombinant fowlpox virus containing the
PSA gene (rF-PSA). All patients on the vaccine arms will, in addition,
receive sargramostim and aldesleukin as part of their vaccination
schedule.
The primary endpoint is to identify immunologic response as measured by
in vitro analysis of the patients peripheral blood cells. The immune
response of cohorts A and B will be analyzed at various times to
determine whether a specific immune response can be affected by the
vaccination as well as whether radiotherapy has an effect on that immune
response. The serum PSA will be followed as a secondary endpoint.
All patients with PSA-expressing adenocarcinoma of the prostate will be
evaluated for eligibility that includes a history of prior vaccinia (as
vaccine against smallpox) and immunocompetence.
Eligibility
Genders Eligible for Study:  Male
Criteria
INCLUSION CRITERIA:
Patients with histologically confirmed diagnosis of adenocarcinoma of
the prostate who are candidates for definitive radiotherapy, who have
not had local therapy but who agree to be treated with radiotherapy
(external beam therapy alone or in combination with brachytherapy).
Patients must be HLA-A2 positive for cohorts A and B. At least 9
patients must be HLA-A2 positive in cohort C.
Zubrod (ECOG) performance 0-1.
Age greater than or equal to 18 years.
Concurrent hormonal therapy will be allowed.
Patients must have received prior vaccinia (for smallpox immunization).
For patients less than 30 years of age, physician certification of prior
smallpox immunization is required. For patients greater than or equal to
age 30, patient recollection and appropriate vaccination-site scar is
sufficient evidence. There must be no history of allergy or untoward
reaction to prior vaccination with vaccinia virus.
Absolute lymphocyte count greater than or equal to 600/mm(3); platelets
greater than or equal to 100,000/mm(3); hemoglobin greater than or equal
to 8.0 grams/dl.
The initial urine analysis for eligibility should be less than or equal
to grade 1 proteinuria, grade 0 hematuria and no abnormal sediment. Any
positive protein, including trace values, should be evaluated by a
24-hour urine less than or equal to 1 gram per 24 hours. Any other
abnormalities in the sediment or the presence of hematuria should be
evaluated by a nephrologist for evidence of underlying renal pathology.
Patients may be eligible if the underlying cause of the abnormality is
determined to be non-renal.
Serum bilirubin less than or equal to 1.6 mg/dl, AST and ALT less than
or equal to 4 times normal; serum creatinine less than or equal to 1.5
mg/dl or a creatinine clearance of greater than 60 ml/min.
Patients must understand and sign informed consent that explains the
neoplastic nature of his disease, the procedures to be followed, the
experimental nature of the treatment, alternative treatments, potential
risks and toxicities, and the voluntary nature of participation.
EXCLUSION CRITERIA:
Patients should have no evidence of being immunocompromised as listed
below:
They should have no reactive HIV testing;
They should not have any other diagnosis of altered immune function,
autoimmune disease (autoimmune neutropenia, thrombocytopenia, or
hemolytic anemia; systemic lupus erythematosus, Sjogren syndrome, or
scleroderma; myasthenia gravis; Goodpasture syndrome; Addison's disease,
Hashimoto's thyroiditis, or active Graves' disease).
They should not have prior radiation therapy greater than 50% of nodal
groups;
They should not have had a prior splenectomy;
They should not be using glucocorticoids (including glucocorticoids for
brachytherapy).
The recombinant vaccinia vaccine should not be administered if the
following apply to either recipients or, for at least two weeks after
vaccination, their close household contacts: Persons with active or a
history of eczema or other eczematoid skin disorders; those with other
acute, chronic or exfoliative skin conditions (e.g., atopic dermatitis,
burns, impetigo, varicella zoster, severe acne or other open rashes or
wound) until condition resolves; Pregnant or nursing women; Children
under 5 years of age; and immunodeficient or immunosuppressed persons
(by disease or therapy) , including HIV infection. Close household
contacts are those who share housing or have close physical contact.
Other serious intercurrent illness. Patients with active infections
requiring antibiotic treatment (including chronic suppressive therapy)
are not eligible until the infection has cleared and the antibiotics
have been stopped for at least three days.
History of other malignant process (excluding squamous cell or basal
cell carcinoma of the skin), unless that previous tumor was treated with
curative intent and the patient has been in remission for at least three
years.
Patients with a history of seizures, encephalitis, or multiple sclerosis
are not eligible.
Patients with known allergy to eggs are not eligible.
Patients should not have any cardiac disease, pulmonary disease,
autoimmune disease, renal disease or hepatic dysfunction that may be
exacerbated by IL-2.
Expected Total Enrollment:  48
Location and Contact Information
Maryland
      National Cancer Institute (NCI), 9000 Rockville
Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting
Clinical Studies Support Center/NCI  1-888-624-1937   
ncicssc@mail.nih.gov 
More Information
Detailed Web Page
Publications
Sanda MG, Smith DC, Charles LG, Hwang C, Pienta KJ, Schlom J, Milenic D,
Panicali D, Montie JE. Recombinant vaccinia-PSA (PROSTVAC) can induce a
prostate-specific immune response in androgen-modulated human prostate
cancer. Urology. 1999 Feb;53(2):260-6.
Wei C, Storozynsky E, McAdam AJ, Yeh KY, Tilton BR, Willis RA, Barth RK,
Looney RJ, Lord EM, Frelinger JG. Expression of human prostate-specific
antigen (PSA) in a mouse tumor cell line reduces tumorigenicity and
elicits PSA-specific cytotoxic T lymphocytes. Cancer Immunol Immunother.
1996 Jul;42(6):362-8.
Matzkin H, Eber P, Todd B, van der Zwaag R, Soloway MS. Prognostic
significance of changes in prostate-specific markers after endocrine
treatment of stage D2 prostatic cancer. Cancer. 1992 Nov 1;70(9):2302-9.
Study ID Numbers  000154;  00-C-0154
Study Start Date June 13, 2000
Record last reviewed  June 1, 2004
Last Updated  June 1, 2004
ClinicalTrials.gov Identifier  NCT00005916
ClinicalTrials.gov processed this record on 2004-09-03
U.S. National Library of Medicine, Contact NLM Customer ServiceNational
Institutes of Health, Department of Health & Human ServicesCopyright,
Privacy, Accessibility, Freedom of Information Act

knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."

Leuvectin Followed By Surgery in Treating Patients With Stage II or
Stage III Prostate Cancer

This study is no longer recruiting patients.

Sponsored by
National Cancer Institute (NCI)
Jonsson Comprehensive Cancer Center
Purpose
RATIONALE: Inserting the gene for interleukin-2 into a person's cancer
cells may improve the body's ability to fight cancer. Using leuvectin to
deliver this gene may be an effective treatment for prostate cancer.
PURPOSE: Phase II trial to study the effectiveness of leuvectin followed
by surgery in treating patients who have stage II or stage III prostate
cancer.
Condition Treatment or InterventionPhasestage II prostate cancer
stage III prostate cancer
 Procedure: surgery
 Procedure: gene therapy
 Procedure: conventional surgery
 Drug: leuvectin
Phase II
MedlinePlus related topics:  Prostate Cancer
Study Type: Interventional
Study Design: Treatment
Official Title: Phase II Study of Neoadjuvant Leuvectin Followed by
Retropubic Prostatectomy in Patients With Stage II or III Prostate
Cancer
Further Study Details: 
OBJECTIVES: I. Assess the toxicity and tolerability of neoadjuvant
leuvectin in patients with stage II or III prostate cancer. II. Evaluate
the efficacy of this regimen in preventing or delaying manifestations of
disease progression as demonstrated by biochemical failure or clinical
recurrence in this patient population.
PROTOCOL OUTLINE: This is a multicenter study. Patients receive
leuvectin intraprostatically over 10-30 seconds under ultrasound
guidance on day 0 followed by a second injection between days 4 and 7.
Between days 8 and 14, patients undergo retropubic prostatectomy. All
patients are followed at 2 months. Patients with a PSA no greater than
0.2 ng/mL are followed at 4 months and 6 months, every 3 months for 12
months, and then every 6 months for 3.5 years in the absence of disease
progression or biochemical failure.
PROJECTED ACCRUAL: Approximately 30 patients will be accrued for this
study.
Eligibility
Ages Eligible for Study:  18 Years and above
Criteria
PROTOCOL ENTRY CRITERIA:
--Disease Characteristics--
Histologically confirmed stage II or III organ confined prostate cancer;
Resectable disease (candidate for retropubic prostatectomy)
Gleason score at least 6
PSA at least 5 ng/mL
No significant CNS disease
--Prior/Concurrent Therapy--
Biologic therapy: Not specified
Chemotherapy: No prior chemotherapy for prostate cancer; At least 5
years since other prior chemotherapy
Endocrine therapy: No prior glucocorticoids for prostate cancer; At
least 5 years since other prior glucocorticoids
Radiotherapy: No prior radiotherapy for prostate cancer; At least 5
years since other prior radiotherapy
Surgery: See Disease Characteristics; At least 4 weeks since prior
intrathoracic or intraabdominal surgery; At least 2 weeks since other
major surgery
Other: At least 10 days since prior anticoagulants or nonsteroidal
antiinflammatory agents; No other neoadjuvant or concurrent anticancer
drugs; No concurrent immunosuppressive drugs; No other concurrent
experimental therapy; No concurrent parenteral antibiotics
--Patient Characteristics--
Age: 18 and over
Performance status: Karnofsky 80-100% ECOG 0-1
Life expectancy: Not specified
Hematopoietic: WBC greater than 3,000/mm3; Platelet count greater than
100,000/mm3; Hemoglobin greater than 9.0 g/dL
Hepatic: Bilirubin normal; SGOT/SGPT less than 3 times upper limit of
normal; PT/PTT normal; Albumin greater than 3.0 g/dL; Hepatitis B
surface antigen negative
Renal: Creatinine normal
Cardiovascular: No uncontrolled hypertension; No significant
cardiovascular disease; No history of ventricular dysfunction or
arrhythmia; No congestive heart failure; No symptoms of coronary artery
disease; No prior myocardial infarction
Other: No active autoimmune disease; No active infection requiring
parenteral antibiotics; HIV negative; No significant psychiatric
disorder that would preclude compliance; No other malignancy within the
past 5 years except curatively treated basal or squamous cell skin
cancer; No diabetes mellitus; Fertile patients must use effective
contraception
Location Information
California
      Jonsson Comprehensive Cancer Center, UCLA, Los
Angeles,  California,  90095-1781,  United States
Ohio
      Cleveland Clinic Taussig Cancer
Center, Cleveland,  Ohio,  44195,  United States
Study chairs or principal investigators
Arie Belldegrun,  Study Chair,  Jonsson Comprehensive Cancer Center
  
More Information
Study ID Numbers  CDR0000067244; 
UCLA-9901077-03A; NCI-G99-1568; VCL-1102-202
Study Start Date June 1999
Record last reviewed  October 2003
ClinicalTrials.gov Identifier  NCT00004050
ClinicalTrials.gov processed this record on 2004-09-03
U.S. National Library of Medicine, Contact NLM Customer ServiceNational
Institutes of Health, Department of Health & Human ServicesCopyright,
Privacy, Accessibility, Freedom of Information Act

knowledge is power - growing old is mandatory - growing wise is optional    
"Many more men die with prostate cancer than of it. Growing old is
invariably fatal. Prostate cancer is only sometimes so."

Bev,

Vaccines are currently a Phase I Trial. As such, it is not approved by the
FDA. Early reports are great....... Those with metastis will have to wait
about two years according to my Research Medical Oncologist. He told me that
cure rates in rats was 100%. Everyway they sliced and diced the tumors the
results were the same, dead cancer cells. It will give another shot at a
cure treatment rather than pallative treatment.

Mike

Bev, Do a search on Provenge and the company Dendreon.