Safety and Outcomes of a Plasmid DNA Vaccine Encoding the ERBB2 Intracellular Domain in Patients With Advanced-Stage ERBB2-Positive Breast Cancer

Abstract

ImportanceHigh levels of ERBB2 (formerly HER2)–specific type 1 T cells in the peripheral blood are associated with favorable clinical outcomes after trastuzumab therapy; however, only a minority of patients develop measurable ERBB2 immunity after treatment. Vaccines designed to increase ERBB2-specific T-helper cells could induce ERBB2 immunity in a majority of patients.ObjectiveTo determine the safety and immunogenicity of 3 doses (10, 100, and 500 μg) of a plasmid-based vaccine encoding the ERBB2 intracellular domain (ICD).Design, Setting, and ParticipantsSingle-arm phase 1 trial including 66 patients with advanced-stage ERBB2-positive breast cancer treated in an academic medical center between 2001 and 2010 with 10-year postvaccine toxicity assessments. Data analysis was performed over 2 periods: January 2012 to March 2013 and July 2021 to August 2022.InterventionsPatients were sequentially enrolled to the 3 dose arms. The vaccine was administered intradermally once a month with soluble granulocyte-macrophage colony-stimulating factor as an adjuvant for 3 immunizations. Toxicity evaluations occurred at set intervals and yearly. Peripheral blood mononuclear cells were collected for evaluation of immunity. Biopsy of vaccine sites at weeks 16 and 36 measured DNA persistence.Main Outcomes and MeasuresSafety was graded by Common Terminology Criteria for Adverse Events, version 3.0, and ERBB2 ICD immune responses were measured by interferon-γ enzyme-linked immunosorbent spot. Secondary objectives determined if vaccine dose was associated with immunity and evaluated persistence of plasmid DNA at the vaccine site.ResultsA total of 66 patients (median [range] age, 51 [34-77] years) were enrolled. The majority of vaccine-related toxic effects were grade 1 and 2 and not significantly different between dose arms. Patients in arm 2 (100 μg) and arm 3 (500 μg) had higher magnitude ERBB2 ICD type 1 immune responses at most time points than arm 1 (10 μg) (arm 2 compared with arm 1, coefficient, 181 [95% CI, 60-303]; P = .003; arm 3 compared with arm 1, coefficient, 233 [95% CI, 102-363]; P < .001) after adjusting for baseline factors. ERBB2 ICD immunity at time points after the end of immunizations was significantly lower on average in patients with DNA persistence at week 16 compared with those without persistence. The highest vaccine dose was associated with the greatest incidence of persistent DNA at the injection site.Conclusions and RelevanceIn this phase 1 nonrandomized clinical trial, immunization with the 100-μg dose of the ERBB2 ICD plasmid-based vaccine was associated with generation of ERBB2-specific type 1 T cells in most patients with ERBB2-expressing breast cancer, and it is currently being evaluated in randomized phase 2 trials.Trial RegistrationClinicalTrials.gov Identifier: NCT00436254

Immunotherapy for HER-2 positive breast cancer

“…During the 10-year follow-up period, median OS and PFS had not been achieved in any group as of press time. In the intermediate-dose group, 100% of stage III patients were still alive at the time of last follow-up ( 83 ).…”

Update Breast Cancer 2022 Part 5 – Early Stage Breast Cancer

“…However, antigens that are known to occur in breast tumors are also the focus of experimental vaccines [11]. Data on a new vaccine based on a DNA plasmid have now been published for the first time [12]. In this phase I study, a DNA plasmid coding for the intracellular domain of the HER2 receptor was tested in various doses [12].…”

“…Data on a new vaccine based on a DNA plasmid have now been published for the first time [12]. In this phase I study, a DNA plasmid coding for the intracellular domain of the HER2 receptor was tested in various doses [12]. The patients enrolled in the study who received the highest dose also recorded the greatest response in terms of a type 1 immune response.…”

“…Aber auch Antigene, die bekannterweise bei Mammakarzinomtumoren vorkommen, stehen im Fokus von Impfbemühungen [11]. Nun sind zum ersten Mal Daten mit einem neuen DNA-Plasmid basierten Vakzin veröffentlicht worden [12]. In dieser Phase-I-Studie wurde ein DNA-Plasmid, das die intrazelluläre Domäne des HER2-Rezeptors kodiert, in verschiedenen Dosen getestet [12].…”

“…Nun sind zum ersten Mal Daten mit einem neuen DNA-Plasmid basierten Vakzin veröffentlicht worden [12]. In dieser Phase-I-Studie wurde ein DNA-Plasmid, das die intrazelluläre Domäne des HER2-Rezeptors kodiert, in verschiedenen Dosen getestet [12]. Bei den eingeschlossenen Patientinnen, welche die höchste Dosis erhielten,…”