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Human T Cells Armed with Her2/neu Bispecific Antibodies Divide, Are Cytotoxic, and Secrete Cytokines with Repeated Stimulation

Authors' Affiliations: ¹ Immunotherapy and Blood and Stem Cell Transplant Programs, Adele R. Decof Cancer Center and Division of Hematology/Oncology, Department of Medicine, Roger Williams Medical Center; ² Department of Medicine, Brown University School of Medicine, Providence, Rhode Island; ³ University of California San Diego School of Medicine, San Diego, California; ⁴ Department of Biostatistics, North Carolina State University, Raleigh, North Carolina; and ⁵ Department of Medicine, Boston University School of Medicine, Boston, Massachusetts

Requests for reprints: Leslie P. Cousens, Roger Williams Medical Center, North Campus, Room G06, 825 Chalkstone Avenue, Providence, RI 02908. Phone: 401-456-6472; Fax: 401-456-2398; E-mail: lcousens{at}rwmc.org.

Purpose: Cancer immunotherapy has been limited by anergy of patient T cells, inadequate numbers of precursor tumor-specific CTL, and difficulty in producing therapeutic doses of CTL. To overcome these limitations, bispecific antibodies have been used to create artificial antibody receptors that direct polyclonal activated T cells (ATC) to target tumor antigens. Studies reported herein were designed to characterize bispecific antibody–armed ATC functions during multiple rounds of targeted cell stimulation.

Experimental Design: ATCs were generated from human peripheral blood mononuclear cells (PBMC) by culture with anti-CD3 and interleukin 2 for 14 days and armed with anti-CD3 x anti-Her2 bispecific antibody (Her2Bi). In vitro, Her2Bi-armed ATC were examined for a range of functions after repeated stimulation with the Her2/neu-expressing breast cancer cell line SK-BR-3. PBMC isolated from cancer patients treated with Her2Bi-armed ATC were tested ex vivo for cytotoxicity against SK-BR-3.

Results: In vitro, armed ATC divided, maintained surface Her2Bi, and expressed a range of activities for extended periods of time. Perforin-mediated cytotoxic activity by armed ATC continued for at least 336 hours, and cytokines and chemokines (i.e., IFN- and regulated on activation, normal T-cell expressed and secreted protein [RANTES]) were secreted during successive rounds of stimulation. Furthermore, PBMC isolated from patients over their courses of immunotherapy exhibited significant cytolytic activity against SK-BR-3 as a function of Her2Bi-armed ATC infusions.

Conclusions: These studies show that armed ATC are specific, durable, and highly functional T-cell populations in vitro. These previously unappreciated broad and long-term functions of armed ATC are encouraging for their therapeutic use in treating cancer.