Human T cells armed with Her2/neu bispecific antibodies divide, are cytotoxic, and secrete cytokines with repeated stimulation
RC Grabert, LP Cousens, JA Smith, S Olson, J Gall… - Clinical Cancer …, 2006 - AACR
Clinical Cancer Research, 2006•AACR
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 …
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 …
Abstract
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 × 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-γ 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.
AACR
