RESUMO
PURPOSE: Patients with HER2+ breast cancer benefit from trastuzumab-containing regimens with improved survival. Adaptive immunity, including cytotoxic T-cell and antibody immunity, is critical to clinical efficacy of trastuzumab. Because Th cells are central to the activation of these antitumor effectors, we reason that HER2 patients treated with trastuzumab may benefit by administering vaccines that are designed to stimulate Th-cell immunity. PATIENTS AND METHODS: We developed a degenerate HER2 epitope-based vaccine consisting of four HLA class II-restricted epitopes mixed with GM-CSF that should immunize most (≥84%) patients. The vaccine was tested in a phase I trial. Eligible women had resectable HER2+ breast cancer and had completed standard treatment prior to enrollment and were disease free. Patients were vaccinated monthly for six doses and monitored for safety and immunogenicity. RESULTS: Twenty-two subjects were enrolled and 20 completed all six vaccines. The vaccine was well tolerated. All patients were alive at analysis with a median follow-up of 2.3 years and only two experienced disease recurrence. The percent of patients that responded with augmented T-cell immunity was high for each peptide ranging from 68% to 88%, which led to 90% of the patients generating T cells that recognized naturally processed HER2 antigen. The vaccine also augmented HER2-specific antibody. Immunity was sustained in patients with little sign of diminishing at 2 years following the vaccination. CONCLUSIONS: Degenerate HLA-DR-based HER2 vaccines induce sustainable HER2-specific T cells and antibodies. Future studies, could evaluate whether vaccination during adjuvant treatment with trastuzumab-containing regimens improves patient outcomes.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Epitopos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Peptídeos/imunologia , Receptor ErbB-2/imunologia , Linfócitos T/imunologia , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Vacinas Anticâncer/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Segurança do Paciente , Peptídeos/química , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/uso terapêutico , Resultado do TratamentoRESUMO
Purpose: Folate receptor alpha (FR) is overexpressed in several cancers. Endogenous immunity to the FR has been demonstrated in patients and suggests the feasibility of targeting FR with vaccine or other immune therapies. CD4 helper T cells are central to the development of coordinated immunity, and prior work shows their importance in protecting against relapse. Our previous identification of degenerate HLA-class II epitopes from human FR led to the development of a broad coverage epitope pool potentially useful in augmenting antigen-specific immune responses in most patients.Patients and Methods: We conducted a phase I clinical trial testing safety and immunogenicity of this vaccine, enrolling patients with ovarian cancer or breast cancer who completed conventional treatment and who showed no evidence of disease. Patients were initially treated with low-dose cyclophosphamide and then vaccinated 6 times, monthly. Immunity and safety were examined during the vaccine period and up to 1 year later.Results: Vaccination was well tolerated in all patients. Vaccine elicited or augmented immunity in more than 90% of patients examined. Unlike recall immunity to tetanus toxoid (TT), FR T-cell responses developed slowly over the course of vaccination with a median time to maximal immunity in 5 months. Despite slow development of immunity, responsiveness appeared to persist for at least 12 months.Conclusions: The results demonstrate that it is safe to augment immunity to the FR tumor antigen, and the developed vaccine is testable for therapeutic activity in most patients whose tumors express FR, regardless of HLA genotype. Clin Cancer Res; 24(13); 3014-25. ©2018 AACR.
Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Vacinas Anticâncer/imunologia , Receptor 1 de Folato/imunologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Vacinas de Subunidades Antigênicas/imunologia , Adulto , Idoso , Sequência de Aminoácidos , Neoplasias da Mama/diagnóstico , Vacinas Anticâncer/administração & dosagem , Terapia Combinada , Citocinas/metabolismo , Epitopos/química , Epitopos/imunologia , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunidade , Imunogenicidade da Vacina , Contagem de Linfócitos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/diagnóstico , Peptídeos/química , Peptídeos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Resultado do Tratamento , Vacinação , Vacinas de Subunidades Antigênicas/administração & dosagemRESUMO
TAP1-TAP2 heterodimeric complexes are recognized as the transporter associated with antigen processing of major histocompatibility complex class I peptides for recognition by tumor-specific cytotoxic T lymphocytes. In this study, we investigated the immunohistochemical expression of TAP1 and TAP2 in 160 patients with breast cancer and correlated their expression levels with clinicopathologic parameters. The median age of the patient cohort was 52.5 years (range, 30-86 years). Both TAP1 and TAP2 immunohistochemical expression levels correlated significantly with breast cancer characteristics (P < .001). TAP1 expression levels were low to negative in stage I breast tumors. TAP1 and TAP2 levels were significantly higher in grade 3 tumors than low-grade (grade 1 and 2) tumors. TAP1 and TAP2 expression levels were not significantly different among different levels of HER2-expressing tumors and did not vary by estrogen and progesterone receptor status or patient age. Both TAP1 and TAP2 overexpression in breast cancer might be an indicator of an aggressive breast tumor.