Timed Sequential Treatment With Cyclophosphamide, Doxorubicin, and an Allogeneic Granulocyte-Macrophage Colony-Stimulating Factor–Secreting Breast Tumor Vaccine: A Chemotherapy Dose-Ranging Factorial Study of Safety and Immune Activation

Abstract

A B S T R A C T PurposeGranulocyte-macrophage colony-stimulating factor (GM-CSF) -secreting tumor vaccines have demonstrated bioactivity but may be limited by disease burdens and immune tolerance. We tested the hypothesis that cyclophosphamide (CY) and doxorubicin (DOX) can enhance vaccine-induced immunity in patients with breast cancer. Patients and MethodsWe conducted a 3 ϫ 3 factorial (response surface) dose-ranging study of CY, DOX, and an HER2-positive, allogeneic, GM-CSF-secreting tumor vaccine in 28 patients with metastatic breast cancer. Patients received three monthly immunizations, with a boost 6 to 8 months from study entry. Primary objectives included safety and determination of the chemotherapy doses that maximize HER2-specific immunity. Results Twenty ConclusionFirst, immunotherapy with an allogeneic, HER2-positive, GM-CSF-secreting breast tumor vaccine alone or with CY and DOX is safe and induces HER2-specific immunity in patients with metastatic breast cancer. Second, the immunomodulatory activity of low-dose CY has a narrow therapeutic window, with an optimal dose not exceeding 200 mg/m 2 . Third, factorial designs provide an opportunity to identify the most active combination of interacting drugs in patients. Further investigation of the impact of chemotherapy on vaccine-induced immunity is warranted.

Allogeneic tumor cell vaccines

“…HER2-specific humoral immunity was enhanced in the serum of patients receiving the vaccine along with 200 mg/m 2 CY or 35 mg/m 2 DOX. 47 These results suggest that low dose chemotherapy can be used to break tolerance, while sustaining an antigen-specific immune response. Moreover, these results are consistent with a working hypothesis that low dose chemotherapy can delay the vaccine specific immune response witnessed after repeated vaccination with allogeneic cells.…”

“…Vaccines consisting of genetically modified tumor cells secreting various cytokines, such as GM-CSF, have previously been shown to be safe and induce an immune response in phase I and phase II clinical trials. 47 However, these responses were not sufficient to overcome the immune suppression induced by established tumors. In order to be effective as a monotherapy, cancer vaccines must be capable of inducing potent and sustainable tumor-specific immune responses that will reduce overall tumor burden.…”

“…The vaccine, formulated from two HER2/neu positive mammary adenocarcinoma breast cancer cell lines (SKBR3 and T47D) 48 were administered either alone or in sequence with common chemotherapeutic agents cyclophosphamide (CY) and doxorubicin (DOX). 47 The goals of the study were to determine the safety of this combinatorial therapy and the optimal chemotherapy dose that would induce enhanced immunity against the breast cancer TAA HER2. 49 This study showed that up to 4 doses were well tolerated by patients, while accompanied by only modest levels of toxicity that was not exacerbated with the addition of chemotherapy.…”

Anti-HER2 vaccines: new prospects for breast cancer therapy

“…The effect of cyclophosphamide is best appreciated at low dose when it acts as an immunostimulator via the elimination and the inactivation of T regs [105]. Recently, Emens et al [107] showed that an allogeneic GM-CSF-secreting breast tumor vaccine is safe and bioactive when given alone or in sequential treatment with low-dose cyclophosphamide and doxorubicin. A larger trial to test the safety and efficacy of vaccine and the optimal chemotherapy dose combination is currently being designed.…”

Immunotherapy of Cancer: Key Findings and Commentary on the Third Tegernsee Conference

“…Leisha A. Emens (Baltimore, MD) and colleagues combined low-dose cyclophosphamide (CY), doxorubicin (DOX), and an allogeneic, human epidermal growth factor receptor (HER)-2 ϩ , GM-CSF-secreting breast tumor vaccine in 28 patients with metastatic breast cancer. She demonstrated that certain chemotherapy regimens (such as CY ϩ DOX) resulted in optimal stimulation and that low-dose chemotherapy can be combined with tumor vaccines to aug-ment immunity, but the therapeutic window for a positive effect seemed narrow [12].…”