Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00194714.

Fig 1.

A human epidermal growth factor receptor 2 (HER2)/neu T-helper peptide vaccine administered concurrently with trastuzumab stimulates or boosts HER2/neu-specific immunity in the majority of patients. (A) Prevaccine (Pre) and maximal (Max) responses 1/frequency (Y axis) tested antigens (X axis). Connected points: mean and SE of six replicates with median bar. Data derived from 10 controls are shown for extracellular domain (ECD) and intracellular domain (ICD). (B) Percent HER2/neu-specific immunity after vaccination. Blue, percent increased; yellow, percent unchanged. ELISPOT, enzyme-linked immunosorbent spot assay.

Fig 2.

Vaccination can elicit tumor-specific cytotoxic T cells. (A) Prevaccine (Pre) and maximal (Max) responses 1/frequency (Y axis) HLA-A2 peptides (X axis). Connected points: mean and SE of six replicates with median bar. (B) Percent lysis: SKBR3 (blue), SKBR3-A2 (yellow) with SE of four replicates. (C) Percent human epidermal growth factor receptor 2 (HER2)/neu peptide-specific immunity. Blue, percent increased; Yellow, percent unchanged. ELISPOT, enzyme-linked immunosorbent spot assay.

Fig 3.

Vaccination-induced epitope spreading occurred in the majority of patients and was associated with a decrease in serum transforming growth factor beta (TGF-β) levels. (A) Prevaccine (Pre) and maximal (Max) intramolecular epitope spreading (IMS) 1/frequency (Y axis) peptides (X axis). (B) Pre-Max intermolecular epitope spreading (Y axis) antigens (X axis). Connected points: mean and standard deviation of six replicates with median bar. (C) X axis, change in magnitude of IMS response (interferon gamma [IFN-γ] spots per well/10⁶ peripheral-blood mononuclear cells [PBMCs]). (D) X axis, change in magnitude of tetanus toxoid response. Y-axis; change in TGF-ß. ELISPOT, enzyme-linked immunosorbent spot assay.

Fig 4.

Overall survival (OS) and progression-free survival (PFS) of immunized patients. Kaplan-Meier curves of the percent OS and PFS in months from the time of first vaccine (n = 21).