Endogenous Cytokine Responses and Unexpected Survival in a Phase I Trial Using Anti-CD3 x Anti-HER2 Bispecific Antibody Armed Activated T Cells (HER2 BATs) for Treatment of Women with Stage III Breast Cancer

Abstract BACKGROUND: Advanced stage breast cancer has unacceptably high recurrence rates. In this study, we report a phase I immunotherapy (IT) trial in women with high risk (>3 positive nodes) breast cancer that seeks to determine safety and maximum tolerated dose (MTD) of anti-CD3 x anti-HER2 bispecific antibody (HER2Bi) armed activated T cells (HER2 BATs), with the secondary objective of determining whether IT induces endogenous cytokine changes. METHODS: The phase I trial consisted of 8 twice weekly infusions of HER2 BATs given in a 3+3 dose escalation with groups of 3 patients receiving 5, 10, or 20 x 109 HER2 BATs per infusion. HER2 BATs were given in combination with daily low dose interleukin 2 (IL-2) and twice weekly low dose granulocyte-macrophage colony-stimulating factor (GM-CSF) to determine safety, the maximum tolerated dose (MTD), technical feasibility, immune cytokine responses, time to progression (TTP), and overall survival (OS). RESULTS: Nine women with stage III breast cancer were enrolled at a single institution. There were no dose limiting toxicities (DLTs) and the MTD was not defined. It was technically feasible to grow 176 x 109 ATC from a single apheresis. Five of 9 women are alive with no evidence of disease with an undefined median OS. Infusions of HER2 BATs induced increases in serum Th1 cytokines, and some of these changes persisted for weeks to months after IT. CONCLUSIONS: Targeting HER2 positive and negative tumors with BATs infusions was safe, induced Th1 cytokines and IL-12 responses in the serum providing evidence for inducing changes in the endogenous immune system of the patients. The prolonged survival that is undefined with a median follow up of 12.7 years suggests that targeting tumors in the adjuvant setting with HER2 BATs may help eliminate microscopic residual disease after surgery, irradiation, and chemotherapy. TRIAL REGISTRATION: The protocol entitled “Combination Chemotherapy Plus Biological Therapy in Treating Patients with Stage II or Stage III Breast Cancer” as a phase I/II was registered January 27, 2003, with NCT00022230 under clinicaltrials.gov.