Results of a Phase Ib Trial of Combination Immunotherapy with a CD8+ T Cell Eliciting Vaccine and Trastuzumab in Breast Cancer Patients

Background: CD8+ T cell-eliciting vaccines are being investigated in breast cancer patients. Preclinical data showed that trastuzumab increases the susceptibility of tumor cells to lysis by vaccine-generated CD8+ T cells, suggesting potential benefit of a combination immunotherapy strategy. The current trial was undertaken to demonstrate the safety of this approach. Methods: This study was designed as a dose-escalation trial enrolling clinically disease-free, human leukocyte antigen A2+ or A3+ , human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Patients received 6-monthly inoculations of GP2+ granulocyte–macrophage colony-stimulating factor (GM-CSF) administered concurrently with standard-of-care trastuzumab. Local and systemic toxicity, as well as left ventricular ejection fraction (LVEF) were monitored. Immunologic responses were assessed in vivo by measuring the local reaction and in vitro using an interferon-γ enzyme-linked immunosorbent spot (ELISPOT) assay. Results: Seventeen disease-free breast cancer patients were vaccinated. There were no dose-limiting or grade 3–5 local or systemic toxicities, and the median LVEF was unchanged from baseline after vaccination. Mean local reaction at initial inoculation was 28 ± 10 mm, increasing to 68 ± 8 mm at the final inoculation (p < 0.01). Mean ELISPOT response to GP2 increased from 47 ± 19 at baseline to 144 ± 60 (p = 0.13) after vaccination. Based on safety and immunologic data, the appropriate dose was determined to be 1000 μg of GP2 + 250 μg of GM-CSF. Conclusion: The GP2 + GM-CSF vaccine is safe and stimulates an immunologic response when administered concurrently with trastuzumab. An ongoing phase II trial is evaluating the efficacy of combining a CD8 T-cell-eliciting vaccine with trastuzumab in HER2-positive breast cancer patients.