Generation of T-Cell Immunity to the HER-2/neu Protein After Active Immunization With HER-2/neu Peptide–Based Vaccines

Abstract

Purpose: The HER-2/neu protein is a nonmutated tumor antigen that is overexpressed in a variety of human malignancies, including breast and ovarian cancer. Many tumor antigens, such as MAGE and gp100, are self-proteins; therefore, effective vaccine strategies must circumvent tolerance. We hypothesized that immunizing patients with subdominant peptide epitopes derived from HER-2/neu, using an adjuvant known to recruit professional antigen-presenting cells, granulocyte-macrophage colony-stimulating factor, would result in the generation of T-cell immunity specific for the HER-2/neu protein.Patients and Methods: Sixty-four patients with HER-2/neu-overexpressing breast, ovarian, or non-smallcell lung cancers were enrolled. Vaccines were composed of peptides derived from potential T-helper epitopes of the HER-2/neu protein admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally. Peripheral-blood mononuclear cells were evaluated at baseline, before vaccination, and after vaccination for antigen-specific T-cell immunity.Immunologic response data are presented on the 38 subjects who completed six vaccinations. Toxicity data are presented on all 64 patients enrolled.Results: Ninety-two percent of patients developed T-cell immunity to HER-2/neu peptides (stimulation index, 2.1 to 59) and 68% to a HER-2/neu protein domain (stimulation index range, 2 to 31). Epitope spreading was observed in 84% of patients and significantly correlated with the generation of a HER-2/neu protein-specific T-cell immunity (P ‫؍‬ .03). At 1-year follow-up, immunity to the HER-2/neu protein persisted in 38% of patients. Conclusion:The majority of patients with HER-2/ neu-overexpressing cancers can develop immunity to both HER-2/neu peptides and protein. In addition, the generation of protein-specific immunity, after peptide immunization, was associated with epitope spreading, reflecting the initiation of an endogenous immune response. Finally, immunity can persist after active immunizations have ended.

Humoral Epitope-Spreading Following Immunization with a HER-2/neu Peptide Based Vaccine in Cancer Patients

“…Analysis of the T cell responses induced on this trial demonstrated that intramolecular epitope-spreading also occurred at the level of the CD4 + T cell (9). However, data presented here demonstrates that immunity also spread to at least one additional breast cancer antigen besides HER-2/neu.…”

“…Epitope-spreading has also been described in cancer, occurring after certain immunotherapies such as vaccines. Although the endpoint of many clinical trials of cancer vaccines is the evolution of measurable immunity, recent evidence suggests that epitope-spreading may be a more significant predictor of effective immunity (9) or even of clinical response (21). The identification of both intra-and intermolecular humoral epitope-spreading epitope has not previously been reported following immunization with a cancer vaccine.…”

“…Patients were assessed at baseline and monthly during active immunization for both HER-2/neu T cell and antibody responses. The generation of HER-2/neu-specific T cell immunity and adverse events associated with the study have been previously reported (9). Thirty-five of the 38 subjects enrolled were evaluable for antibody responses and are reported here.…”

“…The median age of the population was 50 years (range 25-85) and the median time from the patients' last chemotherapy was 6 months (range 1-75). Three vaccine formulations were evaluated, each containing three different peptides (9). One vaccine consisted of peptides derived from the ECD of HER-2/neu; p42-56 (p42), p98-114 (p98), and p328-345 (p328).…”

A new era in anticancer peptide vaccines

“…16,17 Furthermore, naturally occurring, linked CTL and T h epitopes with improved immunogenicity are present in humans, such as human papillomavirus (HPV), 18,19 NY-ESO-1 (a cancer testis antigen), 20 and HER-2/neu. 21,22 One of the major mechanisms for the enhanced vaccine potency of long peptides is most likely that, unlike 8-mer to 10-mer CTL epitopes, these are not able to bind directly to MHC class I molecules, so their presentation to CTL precursors must follow processing by DCs. 2,23 Thus, long-peptide vaccines obviate binding to MHC class Iexpressing, nonspecialized APCs, which often results in transient CTL responses or tolerance.…”