LOS ANGELES--Bioengineered antibodies against HER2 received major
attention at the the 34th Annual Meeting of the American Society of
Clinical Oncology, but other approaches to HER2-expressing tumors are
waiting in the wings. One uses an antitumor peptide vaccine to induce
specific T-cell immunity to HER2. Another uses anti-HER2
immunoliposomes to steer intracellular delivery of antitumor drugs.
Mary L. Disis, MD, and her colleagues at the University of Washington
and the Corixa Corporation in Seattle, are attempting to remove the
bodys tolerance for HER2, which, as a nonmutated
"self" antigen, does not elicit a host immune response in
the majority of cancer patients even when overexpressed on tumor
Dr. Disis reported phase I data showing that a peptide-based vaccine
can safely immunize patients to oncogenic self antigens and induce
production of specific T-cell responses against the HER2 protein.
The hypothesis behind this approach is based on the fact that T cells
recognize antigens as peptide fragments. Dominant epitopes of self
proteins generate tolerance. Subdominant epitopes of self proteins
can induce immunity if they can bind with the major
histocompatibility complex (MHC). "A potential advantage of
vaccines is the ability to elicit both antibody and cellular
tumor-specific immune responses," Dr. Disis said.
The aim of this study was to determine whether immunity to the HER2
oncogenic protein could be elicited in cancer patients by the use of
a peptide-based vaccine. Vaccine strategies directed against
HER-2/neu and other self tumor antigens require development of
methods to overcome naturally occurring immune tolerance to self.
This approach was successful in transgenic cancer-prone mice, who
could be protected from developing cancer by vaccination before
injection of tumor cells.
Dr. Disis is testing vaccine formulations comprised of groups of
peptides derived from the HER2 extracellular or intracellular domain.
These are mixed with GM-CSF as an adjuvant to stimulate
antigen-presenting cells. Patients undergo intradermal immunization
once a month for a total of six immunizations.
The researchers expect to enroll 60 patients in the study. Dr. Disis
reported on 51 patients who have been immunized, 40 with stage III or
IV breast cancer, 10 with ovarian cancer, and one with non-small-cell
lung cancer. To date, 37 patients have received two or more rounds of
the vaccine, 22 have received all six cycles, and 9 are in follow-up.
Of the 22 who have completed treatment, 20 (95%) have developed
significant peptide immunity and 72% have developed protein immunity
with peptide immunization. This is a surrogate measure for the
ability to respond to tumors overexpressing the protein.
Eighteen of these patients (82%) have developed epitope spreading, an
indication that the vaccination was eliciting new immunity to
endogenous HER2 protein, presumably from the patients own
tumors. Epitope spreading correlated significantly with the
development of protein immunity.
Eight of the nine patients on long-term follow-up have persistent
immunity against HER2. "Five of these eight patients have either
augmented the immune response or developed augmented epitope
spreading," Dr. Disis said.
Immune T cells elicited by vaccination were shown to migrate outside
the peripheral circulation, indicating the potential ability to
traffic to the tumor site.
The regimen is associated with little toxicity. Since HER2 is also
expressed on many normal cells, this was a concern. "We looked
carefully at skin and gut reactions in our patients, and no toxicity
related to autoimmune disease was seen," Dr. Disis said.
She said the study had "demonstrated a simple, yet effective,
vaccine strategy for immunizing humans to oncogenic self proteins.
These results lay the foundation for the use of peptide-based
vaccines as a treatment for human malignancy."
Anti-HER2 MoAB Delivers Drug
HER2 is a cell surface receptor and may provide a useful path for
transporting cytotoxic drugs into HER2-overexpressing tumor cells.
John W. Park, MD, and associates at the University of California, San
Francisco, have developed liposomes linked to anti-HER2 monoclonal
antibodies and carrying little bombs of doxorubicin.
"We previously showed that anti-HER2 immunoliposomes (ILs)
efficiently bind to and internalize in HER2-overexpressing cells in
vitro, resulting in intracellular drug delivery. In vivo, doxorubicin-loaded
ILs greatly increase the therapeutic index of doxorubicin by
increasing antitumor efficacy and by reducing systemic toxicity,"
Dr. Park said.
The researchers reported that the doxorubicin-packed ILs were
effective in four different HER2-overexpressing tumor xenograft
models. Effects included growth inhibition, regressions, and cures.
"The anti-HER2 doxorubicin-containing liposomes were
significantly superior to all other treatments tested, including free
doxorubicin, liposomal doxorubicin, anti-HER2 monoclonal antibody
alone, and free doxorubicin plus anti-HER2 monoclonal antibody,"
Dr. Park said.
Studies of the mechanisms by which anti-HER2 immunoliposomes mediate
drug delivery in vivo showed that liposomes and immunoliposomes both
accumulate in tumors, he said, but immu-noliposomes are dispersed
throughout the tumor (particularly within the cytoplasm of tumor
cells) while ordinary liposomes accumulate extracellularly or within
"These results confirm that immuno-liposomes, unlike liposomes,
achieve intracellular drug delivery. This mechanism may account for
the significantly enhanced efficacy of immunoliposomes against
HER2-overexpressing tumors," Dr. Park concluded.