Safety and Outcomes of a Plasmid DNA Vaccine Encoding the ERBB2 Intracellular Domain in Patients With Advanced-Stage ERBB2-Positive Breast Cancer: A Phase 1 Nonrandomized Clinical Trial

Abstract

Importance: High 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.

Objective: To 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 participants: Single-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.

Interventions: Patients 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 measures: Safety 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.

Results: A 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 relevance: In 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 registration: ClinicalTrials.gov Identifier: NCT00436254.

Figure 1.. CONSORT Diagram

Clinical data are presented on all 66 patients. Immunologic data are presented on those who had baseline and at least 1 additional evaluation of immunity assessed during or after vaccination (n = 59). The most common reason for screen fail was lack of ERBB2 positivity.

Figure 2.. Association of Magnitude and Duration of Vaccine-Associated ERBB2 ICD T-Cell Immunity With Dose

Change in magnitude of ERBB2 intracellular domain (ICD) interferon (IFN)-γ responses (y-axis) from baseline over time from enrollment (x-axis) for arms 1, 2, and 3 (10, 100, and 500 μg, respectively). Box plots represent the mean and IQR (25th and 75th percentiles). The number of postenrollment ERBB2 ICD response measures collected per patient ranged from 1 to 5, with a median of 5 measurements; 9 patients had 1 to 3, 11 had 4, and 41 had 5 measurements each. Five patients from arm 1 were excluded from this analysis due to insufficient samples. PBMCs indicates peripheral blood mononuclear cells.

Figure 3.. Overall and Progression-Free Survival of Vaccinated Patients

Probability of overall survival (A) and progression-free survival (B) by months after enrollment is plotted by dose for arms 1, 2, and 3 (10, 100, and 500 μg, respectively). Tick marks indicate censored patients.