A feasibility study of combination therapy with trastuzumab (T), cyclophosphamide (CY), and an allogeneic GM-CSF-secreting breast tumor vaccine for the treatment of HER2+ metastatic breast cancer.

Abstract

2535 Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines are bioactive, but limited by disease burdens and immune tolerance. Cyclophosphamide (CY) augments the activity of a GM-CSF-secreting breast tumor vaccine in ER+ metastatic breast cancer (MBC) patients. HER-2-specific monoclonal antibodies given with GM-CSF-secreting HER-2-targeted vaccination enhance CD8+ effector T cell function and tumor-free survival in immune tolerant neu transgenic mice. Here, we test the hypothesis that CY-modulated vaccination with weekly Trastuzumab (T) can induce clinically-relevant HER-2-specific immunity in HER-2+ MBC patients. Methods: We conducted a single arm, open label, two-stage feasibility study of CY, an allogeneic HER-2+ GM-CSF-secreting breast tumor vaccine, and standard T in patients with measurable/evaluable HER-2+ MBC. Vaccinations were given every 4-6 weeks for 3 cycles, with a 4th vaccination given 6-8 months from trial entry. Primary objectives included safety, bioactivity, and clinical benefit (CB=complete response+partial response+stable disease). A secondary outcome was delayed type hypersensitivity (DTH) to the MHC Class II HER-2 epitopes p369 and p776. This study has a power of 0.86 to detect a CB rate of 0.45 from a null hypothesis rate of 0.20 at an alpha level of 0.08. Results: Twenty patients were vaccinated. 75% received at least 3 vaccinations, and 40% completed all 4 vaccinations. Toxicities were limited to low grade fever, myalgias, injection site reactions, and urticaria. No dose limiting toxicities were observed. The CB rates at 6 months and 1 year were 10/20 (50%, 95% CI:27-72%) and 7/20 (35%, 95%CI:15-59%) respectively. HER-2-specific DTH developed in 7/20 subjects (35%); four (57%, 95% CI:18-90%) of these had a CB. Conclusions: CY-modulated immunotherapy with an allogeneic, HER-2+ GM-CSF-secreting breast tumor vaccine and weekly T is safe, bioactive, and induces new HER-2-specific DTH in HER-2+ MBC patients. The 50% CB rate at 6 months supports further investigation of CY-modulated vaccination with standard T. The GM-CSF-secreting vaccine platform is licensed from Johns Hopkins University to BioSante. The Johns Hopkins University has the potential to receive royalties in the future.