Safety and Preliminary Evidence of Biologic Efficacy of a Mammaglobin-A DNA Vaccine in Patients with Stable Metastatic Breast Cancer

Abstract

Purpose Mammaglobin-A (MAM-A) is overexpressed in 40–80% of primary breast cancers. We initiated a phase 1 clinical trial of a MAM-A DNA vaccine to evaluate its safety and biological efficacy. Experimental Design Breast cancer patients with stable metastatic disease were eligible for enrollment. Safety was monitored with clinical and laboratory assessments. The CD8 T cell response was measured by ELISPOT, flow cytometry, and cytotoxicity assays. Progression-free survival was described using the Kaplan-Meier product limit estimator. Results Fourteen subjects have been treated with the MAM-A DNA vaccine and no significant adverse events have been observed. Eight of fourteen subjects were HLA-A2+, and the CD8 T cell response to vaccination was studied in detail. Flow cytometry demonstrated a significant increase in the frequency of MAM-A-specific CD8 T cells following vaccination (0.9 ± 0.5% vs. 3.8 ± 1.2%, p < 0.001), and ELISPOT analysis demonstrated an increase in the number of MAM-A-specific IFN-γ-secreting T cells (41 ± 32 vs. 215 ± 67 spm, p < 0.001). Although this study was not powered to evaluate progression-free survival, preliminary evidence suggests that subjects treated with the MAM-A DNA vaccine had improved progression-free survival compared to subjects who met all eligibility criteria, were enrolled in the trial, but were not vaccinated because of HLA phenotype. Conclusion The MAM-A DNA vaccine is safe, capable of eliciting MAM-A-specific CD8 T cell responses, and preliminary evidence suggests improved progression-free survival. Additional studies are required to define the potential of the MAM-A DNA vaccine for breast cancer prevention and/or therapy.

Developing a Clinical Development Paradigm for Translation of a Mammaglobin-A DNA Vaccine

“…Results of the trial demonstrate the safety of the mammaglobin-A DNA vaccine, with preliminary evidence to suggest that the mammaglobin-A vaccine is able to induce mammaglobin-A-specific IFN-γ-secreting CD8 T cells in treated patients. These patients also had improved progression-free survival [8].…”

“…A total of 53 patients met all of the eligibility criteria and were enrolled in a Phase I clinical trial between December 2009 and May 2013 [8]. After enrollment, 39 patients were considered screen failures and 14 patients were vaccinated.…”

“…ELISPOT analysis similarly demonstrated a significant increase in the number of mammaglobin-A specific IFN-γ producing CD8 T cells (41 ± 32 vs 215 ± 67 spm; p < 0.001). A comparison between vaccinated patients and patients who were screen failures based on HLA type suggested that mammaglobin-A DNA vaccination was associated with improved progression-free survival [8].…”

The Five Immune Forces Impacting DNA-Based Cancer Immunotherapeutic Strategy

“…However, the lower frequency of expression of these TAAs (HER2/neu: 20%–30% and MUC1: up to 60%) on breast tumors limits a broader application of these TAAs as a viable immunotherapeutic strategy [27,28]. In contrast, the Mam-A, a 10 kDa glycoprotein, is expressed on more than 80% of breast tumors across all individual breast cancer types and stages [18,29]. Further, Mam-A is shown to have exclusive expression on breast cancer cells, with virtually no expression on other tissues, thus making it a uniquely specific marker for detection of breast cancer cell metastasis to draining lymph nodes as compared to other markers (such as HER2/neu and cytokeratin-19) [30].…”

Trial watch: Naked and vectored DNA-based anticancer vaccines

“…107 Fourteen individuals out of 52 originally enrolled in the study could be vaccinated, none of whom experienced severe (Grade 3-4) toxicities. Common Grade 1-2 side effects included vaccine site tenderness (in 1 out of 14 vaccinated patients), rash (in 1 out of 14 vaccinated patients) and the precipitation of shingle episodes (in 2 out of 14 vaccinated patients).…”