T-cells targeted with anti-CD3 x anti-HER2 bispecific antibody for treatment of women with stage IV breast cancer (phase I): Clinical and immune function results.

Abstract

2548 Background: Nontoxic immunologic targeting strategies for the treatment of metastatic breast cancer (MBC) are needed. Anti-CD3 activated T cells (ATC) retargeted (armed) with anti-CD3 x anti-Her2 bispecific antibody HER2Bi) exhibit high levels of specific cytotoxicity, proliferate, and secrete cytokines/chemokines. This study was designed to test the safety, survival, persistence, and trafficking of aATC. Methods: We report a phase I trial in 23 patients (pts) with MBC (Her2 0-3+) who received escalating doses of 5, 10, 20, and 40 x 109Her2Bi armed ATC (aATC) twice per week for 4 weeks totaling 40, 80, 160, and 320 x 109 aATC with 300,000 IU/m2/day of IL-2 and GM-CSF 300 µg/m2 twice weekly beginning 3 days before the 1st infusion and ending 1 week after the last infusion. All 7 of the Her2 3+ pts had prior treatment with trastuzumab and most pts had multiple rounds of chemotherapy. Results: Grade III-IV toxicities (NC Immunotherapy Toxicity) by total episodes for 23 pts in decreasing order were chills (60), headache (17), nausea/vomiting (4), backpain (1) hypertension (1), and death (1) due to digoxin toxicity(1). Serum CEA in 3 of 5, CA27-29 in 4 of 4, and Her2 receptors in 4 of 5 pts tested decreased 15-50%. There was 1 partial response 7 months after therapy. Eleven had stable disease and 10 had progressive disease 12-14 weeks after starting aATC in 22 evaluable pts. The median overall survival was 34.5 months for the whole group, 68.8 months for the Her2 3+ group (7 pts), and 25.6 months for the Her 0-2+ group (15 pts). Infusions induced cytotoxicity directed at SK-BR-3 that persisted >4 months, a Th1 cytokine pattern, and increased IL-12p70 levels. aATC circulate for > 96 hrs and biopsies show that aATC localize to tumors. Conclusions: aATC infusions: 1) are safe; 2) induce endogenous cytotoxicity, anti-tumor antibody, and cytokine responses; 3) circulate for >96 hrs; and 4) traffic to tumors. These results suggest that aATC infusions may improve OS by breaking tolerance and “vaccinating” the pts against breast cancer antigens.