RESUMEN
Cancer vaccines may have the most potential for clinical impact when used in the adjuvant setting when tumor burden is at its lowest. Application of cancer vaccines in the adjuvant setting, however, requires integration of immunization with more standard cytotoxic or cytostatic therapies. Common adjuvant therapies for breast cancer patients, i.e. trastuzumab, bisphosphonates and hormonal agents are often administered over several years requiring concurrent administration of these drugs with active immunization. We questioned whether these common adjuvant therapies would impact a patient's ability to develop tumor specific immunity with vaccination. Immune parameters from 36 subjects were evaluated. We determined these adjuvant therapies have no impact on the ability to develop an immune response specific for HER-2/neu peptides (P>0.1) nor do they have an impact on the magnitude of T cell immunity developed with concurrent vaccination (P>0.1). This is the first report to show that the use of trastuzumab, bisphosphonates and hormonal therapy concurrent with cancer vaccine administration have no impact on either the generation or the magnitude of vaccine induced immunity.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/uso terapéutico , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recuento de Células Sanguíneas , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Receptor ErbB-2/inmunologíaRESUMEN
We questioned whether the incidence or magnitude of the humoral or cellular immune response to the self-tumor antigen HER-2/neu is influenced by the level of HER-2/neu protein overexpression as defined by immunohistochemical staining of tumors in breast cancer patients. We obtained peripheral blood from 104 women with stage II, III, and IV pathologically confirmed HER-2/neu-overexpressing breast cancer. Patients were categorized with +1 (n = 14), +2 (n = 20), or +3 (n = 70) HER-2/neu overexpression by institutional pathologic report. Circulating antibodies to HER-2/neu were evaluated using ELISA. T-cell responses to HER-2/neu were measured using an antigen-specific tritiated thymidine incorporation assay. Eighty-two percent of subjects with HER-2/neu antibodies were +3 overexpressors compared with 18% +2 overexpressors and 0% +1 overexpressors, a highly significant difference (P < 0.001), and there were significant differences in the magnitude of the HER-2/neu-specific antibodies between groups with varying HER-2/neu protein expression (P = 0.022). In addition, 65% of subjects with HER-2/neu-specific T cells were +3 overexpressors compared with 16% +2 overexpressors and 19% +1 overexpressors (P = 0.001). Data presented here indicate that endogenous HER-2/neu-specific humoral and T-cell immunity is greater in patients with +3 protein overexpression in their tumors than in patients with lower levels of HER-2/neu expression. Overexpression of a self-tumor-associated protein is a potential mechanism by which immunogenicity is enhanced and may aid in the identification of biologically relevant proteins to target for immune-based molecular cancer therapies.
Asunto(s)
Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Anciano , Anticuerpos Antineoplásicos/biosíntesis , Neoplasias de la Mama/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Persona de Mediana Edad , Receptor ErbB-2/inmunología , Linfocitos T/inmunologíaRESUMEN
PURPOSE: The primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer. PATIENTS AND METHODS: Twenty-two patients with stage IV HER2/neu-positive breast cancer receiving trastuzumab therapy were vaccinated with an HER2/neu T-helper peptide-based vaccine. Toxicity was graded according to National Cancer Institute criteria, and antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay. Data on progression-free and overall survival were collected. RESULTS: Concurrent trastuzumab and HER2/neu vaccinations were well tolerated, with 15% of patients experiencing an asymptomatic decline in left ventricular ejection fraction below the normal range during combination therapy. Although many patients had pre-existing immunity specific for HER2/neu and other breast cancer antigens while treated with trastuzumab alone, that immunity could be significantly boosted and maintained with vaccination. Epitope spreading within HER2/neu and to additional tumor-related proteins was stimulated by immunization, and the magnitude of the T-cell response generated was significantly inversely correlated with serum transforming growth factor beta levels. At a median follow-up of 36 months from the first vaccine, the median overall survival in the study population has not been reached. CONCLUSION: Combination therapy with trastuzumab and a HER2/neu vaccine is associated with minimal toxicity and results in prolonged, robust, antigen-specific immune responses in treated patients.