RESUMEN
There is enthusiasm for using vaccines to stimulate the immune system to treat cancer. In this article, the authors review the evolution of vaccines evaluated in clinical trials, starting with Phase III trials in metastatic disease and progressing to trials in the adjuvant setting. Data from these trials suggest that cancer vaccines may be more effective in patients with lower volume disease, and data from the E75 peptide vaccine trials suggest that vaccines may be most effective in less aggressive disease.
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Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Neoplasias/patología , Neoplasias/terapia , Vacunación/métodos , Ensayos Clínicos como Asunto , Humanos , Neoplasias/inmunologíaRESUMEN
BACKGROUND: The authors conducted exploratory phase 1-2 clinical trials vaccinating breast cancer patients with E75, a human leukocyte antigen (HLA) A2/A3-restricted HER-2/neu (HER2) peptide, and granulocyte-macrophage colony-stimulating factor. The vaccine is given as adjuvant therapy to prevent disease recurrence. They previously reported that the vaccine is safe and effective in stimulating expansion of E75-specific cytotoxic T cells. Here, they report 24-month landmark analyses of disease-free survival (DFS). METHODS: These dose escalation/schedule optimization trials enrolled lymph node-positive and high-risk lymph node-negative patients with HER2 (immunohistochemistry [IHC] 1-3(+) ) expressing tumors. HLA-A2/A3(+) patients were vaccinated; others were followed prospectively as controls for recurrence. DFS was analyzed by Kaplan-Meier curves; groups were compared using log-rank tests. RESULTS: Of 195 enrolled patients, 182 were evaluable: 106 (58.2%) in the vaccinated group and 76 (41.8%) in the control group. The 24-month landmark analysis DFS was 94.3% in the vaccinated group and 86.8% in the control group (P = .08). Importantly, because of trial design, 65% of patients received a lower than optimal vaccine dose. In subset analyses, patients who benefited most from vaccination (vaccinated group vs control group) had lymph node-positive (DFS, 90.2% vs 79.1%; P = .13), HER2 IHC 1+-2+ (DFS, 94.0% vs 79.4%; P = .04), or grade 1 or 2 (DFS, 98.4% vs 86.0%; P = .01) tumors and were optimally dosed (DFS, 97.3% vs 86.8%; P = .08). A booster program has been initiated; no patients receiving booster inoculations have recurred. CONCLUSIONS: The E75 vaccine has clinical efficacy that is more prominent in certain patients. A phase 3 trial enrolling lymph node-positive patients with HER2 low-expressing tumors is warranted.
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Neoplasias de la Mama/prevención & control , Vacunas contra el Cáncer/inmunología , Recurrencia Local de Neoplasia/prevención & control , Fragmentos de Péptidos/inmunología , Receptor ErbB-2/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Antígeno HLA-A2/sangre , Antígeno HLA-A3/sangre , Humanos , Persona de Mediana Edad , Receptor ErbB-2/análisis , Riesgo , Linfocitos T Citotóxicos/inmunologíaRESUMEN
INTRODUCTION: Immunotherapy, including vaccines targeting the human EGFR2 (HER-2/neu) protein, is an active area of investigation in combatting breast cancer. Several vaccines are currently undergoing clinical trials, most of which are CD8(+) T-cell-eliciting vaccines. AE37 is a promising primarily CD4(+) T-cell-eliciting HER-2/neu breast cancer vaccine currently in clinical trials. AREAS COVERED: This article reviews preclinical investigations as well as findings from completed and ongoing Phase I and Phase II clinical trials of the AE37 vaccine. EXPERT OPINION: Clinical trials have shown the AE37 vaccine to be safe and capable of generating peptide-specific, durable immune responses. This has been shown in patients with any level of HER-2/neu expression. Early clinical findings suggest there may be benefit to AE37 vaccination in preventing breast cancer recurrence.
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Neoplasias de la Mama/terapia , Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/uso terapéutico , Linfocitos Infiltrantes de Tumor/inmunología , Animales , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Vacunas contra el Cáncer/efectos adversos , Femenino , Humanos , Receptor ErbB-2/inmunología , Resultado del TratamientoRESUMEN
We have performed multiple adjuvant clinical trials using immunogenic peptides from the HER2/neu protein (AE37/E75/GP2) plus (GM-CSF) given intradermally to breast cancer patients. Four trials were performed with similar dose-escalation design with increasing doses of peptide (AE37/E75/GP2) and varying amounts of GM-CSF. Dose reductions (DRs) were made for significant local and/or systemic toxicity by decreasing GM-CSF for subsequent inoculations. Ex vivo and in vivo immunologic responses were used to compare groups. Of 132 patients, 39 required DR (30 for robust local reactions [DR-L]). DR patients, particularly DR-L, had greater immune responses both ex vivo and in vivo. Postvaccine delayed-type hypersensitivity in DR-L patients compared with all others was larger for E75 (p = 0.001), AE37 (p = 0.077) and GP2 (p = 0.076). All three peptide vaccines were safe and well-tolerated. These findings have led to a clinically relevant optimal vaccine dosing strategy, which may be applicable to other peptide-based cancer vaccines.
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Adyuvantes Inmunológicos/administración & dosificación , Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/inmunología , Fragmentos de Péptidos/inmunología , Receptor ErbB-2/inmunología , Vacunas de Subunidad/inmunología , Vacunas contra el Cáncer/administración & dosificación , Ensayos Clínicos como Asunto , Femenino , Humanos , Resultado del Tratamiento , Vacunas de Subunidad/administración & dosificaciónRESUMEN
Folate receptor alpha (FR α) is a membrane-bound transport protein with several features which make it an attractive target for cancer immunotherapy. FR α is largely shielded from the immune system in normal tissue but exposed while expressed on a variety of malignancies; it is functionally active in cancer pathogenesis; and it is immunogenic. A variety of different immunotherapeutic methods targeting FR α are being explored to treat cancer. Passive immunotherapy includes monoclonal antibodies, antibodies modified to deliver treatments, and modified T cell therapy. Active immunotherapy has focused on using FR α to increase the immunogenicity of cancer or to generate active FR α-directed immunity through a range of vaccination techniques. We will review the rationale behind targeting immunotherapy to FR α and cover the various techniques designed to do this. Folate receptor alpha (FRα) is a unique tumor-associated antigen (TAA) with many characteristics that make it an attractive target for immunotherapy in cancer. Many different immunotherapeutic modalities utilizing FRα are being explored to treat cancer. The research is in various stages: some are just beyond conception, others have been tried and abandoned, and others still are progressing through human clinical trials. This review will cover immunotherapeutic methods, both active and passive, that target FRα.
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Receptor 1 de Folato/inmunología , Inmunoterapia/métodos , Neoplasias/terapia , Anticuerpos Monoclonales/uso terapéutico , Células Dendríticas/inmunología , Humanos , Inmunización Pasiva , Inmunoterapia ActivaRESUMEN
Regulatory T cells (T(Reg)), CD4(+)CD25(+)FOXP3(+), are implicated in suppressing tumor immune responses. We analyzed peripheral blood lymphocytes (PBL) from breast cancer patients receiving a modified HLA class II HER2/neu peptide (AE37) vaccine for T(Reg) cells and correlated their levels with vaccine-specific immune responses. The mean CD4(+)CD25(+)FOXP3(+) T(Reg) cells decreased in patients with vaccination with no significant difference in serum TGF-ß levels. IFN-γ ELISPOT and DTH increased after vaccination with a good correlation between T(Reg) cell reduction and size of DTH to AE37. The T(Reg) cell reduction and associated immune response suggest that AE37 may be clinically useful.