Enhancement of an Allogeneic GM-CSF-Secreting Breast Cancer Vaccine by Immunomodulatory Doses of Cyclophosphamide and Doxorubicin

摘要

Advanced breast cancer is managed with hormonal agents or conventional cytotoxic drugs, but intrinsic drug resistance ultimately causes treatment failure. We have applied the use of tumor cells genetically modified to secrete GM-CSF to the preclinical neu transgenic mouse model, characterized by spontaneous tumor development and pre-existing immune tolerance to HER-2/neu. Low doses of Cyclophosphamide and Doxorubicin in a specifically timed sequence with vaccine can augment the HER-2/neu-specific, vaccine-activated immune response in these mice, resulting in delayed tumor outgrowth compared to chemotherapy or vaccine alone. I have developed a GM-CSF-secreting breast cancer vaccine for human use, and designed a clinical trial to test it in patients with metastatic breast cancer. I have also designed a companion clinical study to govern the long-term follow-up of study participants. A number of regulatory approvals are in place including the FDA IND the RAC, and the JHM-IRB-4. The immune monitoring assays are under development.