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% to 80% of primary breast cancers. We initiated a phase I clinical trial of a MAM-A DNA vaccine to evaluate its safety and biologic efficacy.

EXPERIMENTAL DESIGN:

Patients with breast cancer 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 (PFS) 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 14 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 after 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 IFNγ-secreting T cells (41 ± 32 vs. 215 ± 67 spm; P < 0.001). Although this study was not powered to evaluate progression-free survival (PFS), preliminary evidence suggests that subjects treated with the MAM-A DNA vaccine had improved PFS compared with 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 PFS. Additional studies are required to define the potential of the MAM-A DNA vaccine for breast cancer prevention and/or therapy.

• Authors: Venkataswarup Tiriveedhi, Natalia Tucker, John Herndon, Lijin Li, Mark Sturmoski, Matthew Ellis, Cynthia Ma, Michael Naughton, A Craig Lockhart, Feng Gao, Timothy Fleming, Peter Goedegebuure, Thalachallour Mohanakumar, William E Gillanders
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 23 Pg. 5964-75 (Dec 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25451106 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Biomarkers
• Cancer Vaccines
• Epitopes, T-Lymphocyte
• KLRK1 protein, human
• Mammaglobin A
• NK Cell Lectin-Like Receptor Subfamily K
• Tumor Necrosis Factor-alpha
• Vaccines, DNA
• Interferon-gamma

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers
• Breast Neoplasms (immunology, mortality, pathology, therapy)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cancer Vaccines (administration & dosage, adverse effects, genetics, immunology)
• Combined Modality Therapy
• Cytotoxicity, Immunologic
• Epitopes, T-Lymphocyte (immunology)
• Female
• Genetic Vectors (genetics)
• Humans
• Interferon-gamma (metabolism)
• Male
• Mammaglobin A (genetics, immunology)
• Middle Aged
• NK Cell Lectin-Like Receptor Subfamily K (metabolism)
• Neoplasm Metastasis
• Treatment Outcome
• Tumor Necrosis Factor-alpha (metabolism)
• Vaccination
• Vaccines, DNA (administration & dosage, adverse effects, genetics, immunology)