Increasing doses of cyclophosphamide suppress antigen-specific T helper-dependent immunity induced by a GM-CSF-secreting breast tumor vaccine

Abstract

3009 Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccines have shown promise, but their activity is limited by immune tolerance. We tested the hypothesis that integrating vaccination with cyclophosphamide (CY) and doxorubicin (DOX) can enhance vaccine activity. Methods: We conducted a 3-by-3 factorial dose-ranging study of CY and DOX with an allogeneic, HER-2+ GM-CSF-secreting breast tumor vaccine in patients with stable metastatic breast cancer. CY was given at doses of 200, 250, and 350 mg/m2, and DOX at 15, 25, and 35 mg/m2. Subjects received three monthly immunizations, and a boost 6 to 8 months later. CY was given Day -1, vaccination Day 0, and DOX Day +7. Vaccine-induced HER-2-specific immunity was measured by delayed type hypersensitivity (DTH) to the HER-2-derived MHC Class II peptide epitopes p369 and p776. HER-2-specific antibody was measured by ELISA. Results: Twenty-seven individuals received at least 1 immunization with vaccine alone (6 subjects), or combined with low dose chemotherapy (21 subjects); 14 individuals received 4 vaccinations. Four of 6 subjects (66%) receiving vaccine alone developed HER-2-specific DTH, whereas 4 of 7 (57%) subjects receiving it with 200 mg/m2 CY developed a post- vaccination DTH (p=0.587, 1-sided Fisher’s exact test). However, higher doses of CY (250 or 350 mg/m2) one day before vaccination completely suppressed vaccine-induced DTH compared to vaccine alone or with 200 mg/m2 CY (p=0.007). Significant HER-2-specific humoral immunity developed in 3 of 5 (60%) evaluated subjects who received vaccine with 200 mg/m2 CY, but only 1 subject receiving higher CY doses. DOX did not impact the development of DTH or humoral immunity. Conclusions: Vaccination with an allogeneic, GM-CSF-secreting tumor vaccine with or without CY and DOX induced HER-2-specific DTH in patients with metastatic breast cancer. CY at 200 mg/m2 was associated with the development of humoral immunity. Doses of CY higher than 200 mg/m2 suppressed vaccine-induced HER-2-specific DTH, whereas DOX had no influence. Further investigation of the impact of chemotherapy on distinct measures of vaccine-induced antigen-specific immunity is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cell Genesys, Incorporated