Prime-boost vaccination
with plasmid and adenovirus gene vaccines control HER2/neu+ metastatic breast cancer in mice.
Wang X, Wang JP, Rao XM, Price JE, Zhou HS, Lachman LB.
Department of Experimental Therapeutics, The University
of Texas MD Anderson
Cancer Center,
Houston, TX, USA.
xiaoyanwang@mdanderson.org
INTRODUCTION: Once metastasis has occurred, the possibility of completely
curing breast cancer is unlikely, particularly for the 30 to 40% of cancers
overexpressing the gene for HER2/neu. A vaccine
targeting p185, the protein product of the HER2/neu gene, could have
therapeutic application by controlling the growth and metastasis of highly
aggressive HER2/neu+ cells. The purpose of this study was to determine the
effectiveness of two gene vaccines targeting HER2/neu in preventive and
therapeutic tumor models. METHODS: The mouse breast cancer cell line A2L2,
which expresses the gene for rat HER2/neu and hence p185, was injected into
the mammary fat pad of mice as a model of solid tumor growth or was
injected intravenously as a model of lung metastasis. SINCP-neu, a plasmid containing Sindbis
virus genes and the gene for rat HER2/neu, and Adeno-neu,
an E1,E2a-deleted adenovirus also containing the
gene for rat HER2/neu, were tested as preventive and therapeutic vaccines.
RESULTS: Vaccination with SINCP-neu or Adeno-neu before tumor challenge with A2L2 cells
significantly inhibited the growth of the cells injected into the mammary
fat or intravenously. Vaccination 2 days after tumor challenge with either
vaccine was ineffective in both tumor models. However, therapeutic
vaccination in a prime-boost protocol with SINCP-neu
followed by Adeno-neu significantly prolonged the
overall survival rate of mice injected intravenously with the tumor cells.
Naive mice vaccinated using the same prime-boost protocol demonstrated a
strong serum immunoglobulin G response and p185-specific cellular immunity,
as shown by the results of ELISPOT (enzyme-linked immunospot)
analysis for IFNgamma. CONCLUSION: We report
herein that vaccination of mice with a plasmid gene vaccine and an adenovirus
gene vaccine, each containing the gene for HER2/neu, prevented growth of a
HER2/neu-expressing breast cancer cell line injected into the mammary fat
pad or intravenously. Sequential administration of the vaccines in a
prime-boost protocol was therapeutically effective when tumor cells were
injected intravenously before the vaccination. The vaccines induced high
levels of both cellular and humoral immunity as
determined by in vitro assessment. These findings indicate that clinical
evaluation of these vaccines, particularly when used sequentially in a
prime-boost protocol, is justified.
PMID: 16168101 [PubMed - in process]
Role of HER2/HER3
co-receptor in breast carcinogenesis.
Way TD, Lin JK.
1Institute of Biochemistry and Molecular Biology, College of Medicine,
National Taiwan University, No. 1, Section 1, Jen-ai
Road, Taipei 10018, Taiwan. , 2 jklin@ha.mc.ntu.edu.tw.
ErbB receptors are essential mediators of cell
proliferation and differentiation. Their aberrant activation is associated
with the development and severity of many cancers. Homo- and heterodimerization of ErbB
receptors result in a wide variety of cellular signal transduction. Dimerization of human epidermal growth-factor receptor
(HER)2 and HER3 occurs frequently and is a
preferred heterodimer. The HER2/HER3 dimer constitutes a high affinity co-receptor for heregulin, which is capable of potent mitogenic signaling. HER3 is a kinase-defective
protein that is phosphorylated by HER2. Tyrosine phosphorylated HER3 is able to directly couple to phosphatidylinositide 3-kinase, a lipid kinase involved in the proliferation, survival,
adhesion and motility of tumor cells. The authors' research provides
mechanistic evidence that apigenin induces
apoptosis by depleting the HER2 protein and, in turn, suppressing the
signaling of the HER2/HER3-phosphatidylinositide 3-kinase/Akt pathway. This
indicates that inhibition of HER2/HER3 heterodimer
function may be an especially effective and unique strategy for blocking
the HER2-mediated carcinogenesis of breast cancer cells.
PMID: 16556064 [PubMed - in process]
Combined Radioimmunotherapy and
Chemotherapy of Breast Tumors with Y-90-Labeled Anti-Her2 and Anti-CEA
Antibodies with Taxol.
Crow DM, Williams L,
Colcher
D, Wong JY, Raubitschek
A, Shively JE.
Department of Radioimmunotherapy, Division of
Radiation Oncology, City of Hope National Medical Center, Duarte,
California 91010, Division of Radiology, City of Hope National Medical
Center, Duarte, California 91010, and Division of Immunology, Beckman
Research Institute of the City of Hope, Duarte, California 91010.
Because breast cancer cells often express either Her2/neu or carcinoembryonic antigen (CEA) or both, these tumor
markers are good targets for radioimmunotherapy
using Y-90-labeled antibodies. We performed studies on nude mi
ce
bearing xenografts from MCF7, a cell line that
has low Her2 and CEA expression, to more accurately reflect the more usual
situation in breast cancer. Although uptake of In-111 anti-CEA into tumors
was lower than that for In-111-labeled anti-Her2, radioimmunotherapy
(RIT) with Y-90 anti-CEA was equivalent to that of Y-90 anti-Her2. When
either Y-90 antibody was combined with a split-dose treatment with Taxol, the antitumor effect
was greater than with either agent alone. When Y-90 anti-CEA was combined
with a single dose of Taxol, the results were
equivalent to the split-dose regimen. RIT plus cold Herceptin
had no additional effects on tumor size reduction over RIT alone. When
animals were first treated with Y-90 anti-Her2 and imaged 1-2 weeks later
with In-111 anti-CEA or anti-Her2, tumor uptake was higher for anti-CEA and
improved over tumor uptake with no prior RIT. These results suggest that a
split dose of RIT with anti-Her2 antibody followed by anti-CEA antibody
would be more effective than a single dose of either. This prediction was
partially confirmed in a controlled study comparing single- vs split-dose anti-Her2 RIT followed by either
anti-Her2 or anti-CEA RIT. These studies suggest that combined RIT and Taxol therapy are suitable in breast cancers expressing
either low amounts of Her2 or CEA, thus expanding the number of eligible
patients for combined therapies. They further suggest that split-dose RIT
using different combinations of Y-90-labeled antibodies is effective in antitumor therapy.
PMID: 16173788 [PubMed - as supplied by
publisher]
.
Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA
specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas.
von Minckwitz G, Harder S, Hovelmann
S, Jager
E, Al-Batran SE, Loibl
S, Atmaca
A, Cimpoiasu
C, Neumann A,
Abera
A, Knuth A, Kaufmann M,
Jager
D, Maurer AB,
Wels
WS.
Department of Gynecology and Obstetrics, University Hospital
Frankfurt, Germany.
INTRODUCTION: ScFv(FRP5)-ETA is a recombinant antibody toxin with binding
specificity for ErbB2 (HER2). It consists of an N-terminal single-chain
antibody fragment (scFv), genetically linked to
truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against
ErbB2-overexpressing tumor cells was previously demonstrated in vitro and
in animal models. Here we report the first systemic application of scFv(FRP5)-ETA
in human cancer patients. METHODS: We have performed a phase I dose-finding
study, with the objective to assess the maximum tolerated dose and the
dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen
patients suffering from ErbB2-expressing metastatic
breast cancers, prostate cancers, head and neck cancer, non small cell lung
cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4,
10, 12.5, and 20 microg/kg scFv(FRP5)-ETA were
administered as five daily infusions each for two consecutive weeks.
RESULTS: No hematologic, renal, and/or
cardiovascular toxicities were noted in any of the patients treated.
However, transient elevation of liver enzymes was observed, and considered
dose limiting, in one of six patients at the maximum tolerated dose of 12.5 microg/kg, and in two
of three patients at 20 microg/kg. Fifteen
minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 microg/kg, indicating that predicted therapeutic levels
of the recombinant protein can be applied without inducing toxic side
effects. Induction of antibodies against scFv(FRP5)-ETA
was observed 8 days after initiation of therapy in 13 patients
investigated, but only in five of these patients could neutralizing
activity be detected. Two patients showed stable disease and in three
patients clinical signs of activity in terms of signs and symptoms were
observed (all treated at doses > or = 10 microg/kg).
Disease progression occurred in 11 of the patients. CONCLUSION: Our results
demonstrate that systemic therapy with scFv(FRP5)-ETA can be
safely administered up to a maximum tolerated dose of 12.5 microg/kg in patients with ErbB2-expressing tumors,
justifying further clinical development.
PMID: 15611632 [PubMed - as supplied by
publisher]
Mutations in BRCA1 and BRCA2 show different
expressivity wit
h respect to cancer risk, and
allelic heterogeneity may be present in both genes. We collected 179
pedigrees with identified germline mutation (104
BRCA1 and 75 BRCA2), ascertained in six collaborating centers of the
Italian Consortium for Hereditary Breast and Ovarian Cancer. Significant
heterogeneity was detected for several variables, and a logistic regression
model including age of diagnosis in the proband,
presence of ovarian cancer in the family, presence of prostate or
pancreatic cancer in the family, and presence of male breast cancer in the
family proved to be effective in predicting the presence of a mutation in a
gene rather than the other. Excess of familial aggregation of both breast
and ovarian cancer was observed in both genes. Proportion of ovarian cancer
was increased in the 5' portion of BRCA1, and presence of prostate or
pancreatic cancer in a family was correlated with presence of ovarian
cancer in BRCA2
PMID: 14531499 [PubMed - in process]
Cancer:
