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Reviews
on Recent Clinical Trials
ISSN: 1574-8871
OPEN ACCESS PLUS
Contents
Parallel Conduction of the Phase I Preventive and
Therapeutic Trials Based on the Tat Vaccine Candidate,
2009, 4, 195-204
S. Bellino, V. Francavilla, O. Longo, A.
Tripiciano, G. Paniccia, A. Arancio, V. Fiorelli, A. Scoglio,
B. Collacchi, M. Campagna, A. Lazzarin, G. Tambussi, C. Tassan
Din, R. Visintini, P. Narciso, A. Antinori, G. D’Offizi,
M. Giulianelli, M. Carta, A. Di Carlo, G. Palamara, M. Giuliani,
M.E. Laguar-dia, P. Monini, M. Magnani, F. Ensoli and
B. Ensoli
[Abstract] [Full
text article]
Molecular Pathology of Sarcomas, 2009, 4,
12-26
Daniel Osuna and Enrique de Álava
[Abstract] [Full
text article]
Current Status and Perspectives Regarding the Treatment
of Osteosarcoma: Chemotherapy, 2008, 3, 228-231
Akio Sakamoto and Yukihide Iwamoto
[Abstract] [Full
text article]
Systematic Reviews of Animal Experiments Demonstrate
Poor Contributions Toward Human Healthcare, 2008,
3, 89-96
Andrew Knight
[Abstract] [Full
text article]
Clinical Trials of Cancer Therapies Targeting Prostate-Specific
Membrane Antigen, 2007, 2, 182-190
William C. Olson, Warren D.W. Heston and Ayyappan
K. Rajasekaran
[Abstract]
[Full
text article]
Abstracts
[Back to top]
Parallel Conduction of the Phase I Preventive and
Therapeutic Trials Based on the Tat Vaccine Candidate
S. Bellino, V. Francavilla, O. Longo, A.
Tripiciano, G. Paniccia, A. Arancio, V. Fiorelli, A. Scoglio,
B. Collacchi, M. Campagna, A. Lazzarin, G. Tambussi, C. Tassan
Din, R. Visintini, P. Narciso, A. Antinori, G. D’Offizi,
M. Giulianelli, M. Carta, A. Di Carlo, G. Palamara, M. Giuliani,
M.E. Laguar-dia, P. Monini, M. Magnani, F. Ensoli and
B. Ensoli
[Full
text article]
The native HIV-1 Tat protein was chosen as vaccine candidate
for phase I clinical trials in both uninfected (ClinicalTrials.gov
identifier: NCT00529698) and infected volunteers (ClinicalTrials.gov
identifier: NCT00505401). The rationale was based on the role
of Tat in the natural infection and AIDS pathogenesis, on
the association of Tat-specific immune responses with the
asymptomatic stage and slow-progression rate as well as on
its sequence conservation among HIV clades (http://www.hiv1tat-vaccines.info/).
The parallel conduction in the same clinical centers of randomized,
double blind, placebo-controlled phase I studies both in healthy,
immunologically competent adults and in HIV-infected, clinically
asymptomatic, individuals represents a unique occasion to
compare the vaccine-induced immune response in both the preventive
and therapeutic setting. In both studies, the same lot of
the native Tat protein was administered 5 times, every four
weeks, subcute (SC) with alum adju-vant or intradermic (ID),
in the absence of adjuvant, at 7.5 μg, 15 μg or
30 μg doses, respectively. The primary and secon-dary
endpoints of these studies were the safety and immunogenicity
of the vaccine candidate, respectively. The study lasted 52
weeks and monitoring was conducted for on additional 3 years.
The results of both studies indicated that the Tat vaccine
is safe and well tolerated both locally and systemically and
it is highly immunogenic at all the dosages and by both routes
of administration.
Vaccination with Tat induced a balanced immune response in
uninfected and infected individuals. In particular, therapeutic
immunization induced functional antibodies and partially reverted
the marked Th1 polarization of anti-Tat immunity seen in natural
infection, and elicited a more balanced Th1/Th2 immune response.
Further, the number of CD4 T cells corre-lated positively
with anti-Tat antibody titers.
Based on these results, a phase II study is ongoing in infected
drug-treated individuals (http://www.hiv1tat-vaccines.info/).
[Back to top]
Molecular Pathology of Sarcomas
Daniel Osuna and Enrique de Álava
[Full
text article]
Bone and soft tissue sarcomas are an infrequent group of tumours
with a prevalence of 4 in 100000 people/year. Sarcomas, such
as synovial sarcoma, Ewing’s sarcoma and osteosarcoma,
are more usual in adolescents or in young adults. Neoplasias
such as leiomyosarcoma or liposarcoma are more frequent in
patients over 55 years. One relevant topic is related to sarcomagenesis
elucidation, a key for discovering the early molecular mechanisms
involved in the development of sarcomas as well as the identification
of reliable molecular markers and possible therapeutic targets.
Today, it is known that the cellular context contributes to
the phenotype. Analysis of gene expression profiling of human
sarcomas revealed tightly clustered groups and could denote
the existence of common signalling pathways for each branch.
From the molecular point of view, these neoplasias are grouped
into two main types: (a) sarcomas showing specific genetic
alterations and relatively simple karyotypes, and translocations
which originate gene fusions (e.g., EWS-FLI1 in Ewing’s
sarcoma); or specific genetic mutations (e.g., c-kit in the
gastrointestinal stromal tumour), and (b) sarcomas showing
unspecific gene alterations and very complex karyotypes, and
very numerous gains and losses. This review points out the
clinical projection of sarcomagenesis elucidation and knowledge
of diverse types of molecular alterations.
[Back to top]
Current Status and Perspectives Regarding the Treatment of
Osteosarcoma: Chemotherapy
Akio Sakamoto and Yukihide Iwamoto
[Full
text article]
Osteosarcoma is the most common primary bone tumor
in childhood and adolescence. The use of combination chemotherapy
and surgery enables long-term survival in approximately 60-70%
of cases. However, the necessity for surgery, the poor prognosis
of patients with metastatic or recurrent disease (long-term
survival in only about 20% of cases), and the lack of establishment
of second-line chemotherapy suggest that improvements in chemotherapy
are desperately needed. Currently, in an effort to extend
the protocol with the chemotherapy drugs that already exist,
high-dose chemo-therapy with/without autologous peripheral
blood stem cell transplantation, and tumor-targeted drug delivery
systems are under investigation. Future drug developments
will no doubt lie in the direction of immunotherapy and anti-angiogenic
therapy, as well as the use of cytotoxic drugs. Identifying
the genes and signal transduction pathways responsible for
the development of osteosarcoma or for the occurrence of malignancy
in cases of osteosarcoma will undoubtedly lead to the identification
of pathway-specific agents, or possible gene therapy. Furthermore,
as increased light is shed on the character of osetoblastic
differentiation in osteosarcoma, this will certainly give
rise to new treatments utilizing differentiation therapy.
This article reviews the current status and perspectives regarding
the treatment of osteosarcoma in terms of chemotherapy.
[Back to top]
Systematic Reviews of Animal Experiments Demonstrate
Poor Contributions Toward Human Healthcare
Andrew Knight
[Full
text article]
Widespread reliance on animal models during preclinical research
and toxicity testing assumes their reasonable predictivity
for human outcomes. However, of 20 published systematic reviews
examining human clinical utility, located during a comprehensive
literature search, animal models demonstrated significant
potential to contribute toward the development of clinical
interventions in only two cases, one of which was contentious.
Included were experiments expected by ethics committees to
lead to medical advances, highly-cited experiments published
in major journals, and chimpanzee experiments—the species
most generally predictive of human outcomes. Seven additional
reviews failed to demonstrate utility in reliably predicting
human toxicological outcomes such as carcinogenicity and teratogenicity.
Results in animal models were frequently equivocal, or inconsistent
with human outcomes. Consequently, animal data may not generally
be considered useful for these purposes. Regulatory acceptance
of non-animal models is normally conditional on formal scientific
validation. In contrast, animal models are simply assumed
to be predictive of human outcomes. These results demonstrate
the invalidity of such assumptions. The poor human clinical
and toxicological utility of animal models, combined with
their generally substantial animal welfare and economic costs,
necessitate considerably greater rigor within animal studies,
and justify a ban on the use of animal models lacking scientific
data clearly establishing their human predictivity or utility.
[Back to top]
Clinical Trials of Cancer Therapies Targeting Prostate-Specific
Membrane Antigen
William C. Olson, Warren D.W. Heston and
Ayyappan K. Rajasekaran
[Full
text article]
Prostate cancer is the most common non-cutaneous cancer
of men in the United States and represents their second-leading
cause of cancer-related death. Metastatic disease is largely
resistant to conventional chemotherapies, and targeted therapies
are urgently needed. Prostate-specific membrane antigen (PSMA)
is a prototypical cell-surface marker of prostate cancer.
PSMA is an integral, non-shed, type 2 membrane protein with
abundant and nearly universal expression in prostate carcinoma,
but has limited extra-prostatic expression. In addition, PSMA
is expressed in the neovasculature of other solid tumors.
These findings have spurred development of PSMA-targeted therapies
for cancer, and first-generation products have entered clinical
testing. Vaccine approaches have included recombinant protein,
nucleic acid and cell-based strategies, and anti-PSMA immune
responses have been demonstrated in the absence of significant
toxicity. Therapy with drug-conjugated and radiolabeled antibodies
has yielded objective clinical responses as measured by reductions
in serum prostate-specific antigen and/or imageable tumor
volume. However, responses were observed in a minor fraction
of patients and at doses near the maximum tolerated dose.
Overall, these initial studies have provided measured proof
of concept for PSMA-based therapies, and second-generation
antibody and vaccine products may hold the key to exploit
PSMA for molecularly targeted therapy of prostate and other
cancers.
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