Phase Ib trial: Mam-A DNA vaccine plus endocrine therapy induces T cells in ER+ breast cancer

Tumor-associated antigen (TAA) vaccines are being explored as a strategy to induce antitumor immune responses. Mammaglobin-A (Mam-A) is a TAA expressed in >50% of patients with breast cancer. Previously, we have shown that Mam-A DNA vaccines induce antitumor immune responses in patients with stable metastatic disease. To further evaluate the potential of the Mam-A vaccine, we initiated a phase Ib clinical trial in patients with estrogen receptor-positive breast cancer prior to surgery. Eight patients were assigned to arm 1 (neoadjuvant endocrine therapy alone) and 17 to arm 2 (neoadjuvant endocrine therapy plus Mam-A vaccination); the final analysis included 8 patients from arm 1 and 13 from arm 2. Ex vivo enzyme-linked immunospot (ELISpot) analysis of peripheral blood mononuclear cells demonstrated that Mam-A vaccination induced Mam-A-specific T cells in 8 of 13 patients. Intracellular cytokine staining and Mam-A-specific tetramer staining revealed that vaccine-induced Mam-A-specific T cells included both CD4+ and CD8+ polyfunctional T cells. Finally, high-throughput imaging mass cytometry identified 24 cellular metaclusters with features of tumor, immune, stromal, and endothelial cells and revealed an increased CD8+ T-cell prevalence in the tumor after Mam-A vaccination. In particular, vaccination was associated with the infiltration of PD-1+CD8+ T cells. In addition, postvaccination tumor samples exhibited close spatial interactions between cytotoxic CD8+ T cells (CTL) and Mam-A+ tumor cells and between CTL and antigen-experienced CD4+ T cells. Together, these results suggest that Mam-A DNA vaccination elicits both systemic and intratumoral antitumor immune responses.