Abstract
BackgroundThe HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. Additionally, the beneficial effect of trastuzumab is expected to decrease once the drug is discontinued. We proposed to address these concerns by using cancer vaccines to stimulate HER2 intracellular domain (ICD)-specific T cell and antibody responses.MethodsSubjects with stage II (≥ 6 +LN), III, or stage IV breast cancerwith > 50% HER2 overexpressing tumor cells who were disease-free after surgery and adjuvant therapy were eligible. Vaccines consisted of immature, cultured DC (n = 3), mature cultured DC (n = 3), or mature Flt3-ligand mobilized peripheral blood DC (n = 1) loaded with ICD, or tetanus toxoid, keyhole limpet hemocyanin or CMV peptide as controls, and were administered intradermally/subcutaneously four times at 3 week intervals. ICD-specific T cell and antibody responses were measured. Cardiac function was determined by MUGA or ECHO; long term disease status was obtained from patient contact.ResultsAll seven patients successfully underwent DC generation and five received all 4 immunizations. There were no toxicities greater than grade 1 or ejection fraction decrements below normal. Delayed-type hypersensitivity (DTH) reactions at the injection site occurred in 6/7 patients and HER2 specificity was detected by cytokine flow cytometry or ELISPOT in 5 patients. At more than 5 years of follow-up, 6/7 had detectable anti-ICD antibodies. One patient experienced a pulmonary recurrence at 4 years from their study immunizations. This recurrence was resected and they are without evidence of disease. All patients are alive and disease-free at 4.6–6.7 years of follow-up.ConclusionAlthough this was a small pilot study, the well-tolerated nature of the vaccines, the lack of cardiac toxicity, significant immunogenicity, and a 100% 4.5-year survival rate suggest that vaccination with HER2 ICD protein-containing DC is appropriate for further study in this population.Trial RegistrationClinicalTrials.gov NCT00005956
Highlights
The HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy
A vaccine consisting of a peptide derived from the extracellular domain of HER2 (E75 peptide (HER2 369–377)) mixed with GM-CSF was administered at various doses and schedules to patients with resected node positive and node negative breast cancer
Cardiotoxicity due to the immunizations was not reported, despite the fact that two patients had received trastuzumab and the majority had received prior anthracyclines. In this small pilot study, we observed that dendritic cells (DC) vaccines loaded with HER2 intracellular domain (ICD) protein are well tolerated, induce Delayed-type hypersensitivity (DTH), T cell, and antibody responses, and are associated with long term-disease-free survival
Summary
The HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. The effect of trastuzumab is only expected to persist while it remains at clinically relevant concentrations For these reasons, we sought to study the role of an alternative strategy to target the intracellular domain (ICD) of HER2 via stimulation of HER2-specific T cell and antibody responses using cancer vaccines. More than a dozen phase I and phase II studies have been conducted in breast cancer patients with cancer vaccines [3], that have included proteins, peptides, modified tumor cells, and dendritic cells loaded with breast tumor antigens. In these studies, HER2 has been demonstrated to be immunogenic [4,5,6,7,8,9,10,11,12,13]. The recurrence rate for the vaccinated patients was 5.6% compared to 14.8% for an observational group of patients at a median of 24 months [12,13]
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