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 body’s 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 cells.
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.
Persistent 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(Drug information on 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 macrophages.
"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.
