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Cited by 79Immunotherapy and Immune ResponsesMonoclonal and Polyclonal Antibodies ResearchT-cell and B-cell Immunology

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

Grabert, Ryan C., Cousens, Leslie P., Smith, Janelle A., Olson, Sarah, Gall, Jonathan, Young, Wendy B., Davol, Pamela A., Lum, Lawrence G.·2006·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-05-2005
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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.

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Crossref · 10.1158/1078-0432.ccr-05-2005

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  • Bispecific antibody-retargeted PACTs can divide and secrete cytokines upon restimulation with target cells, while retaining their specificity and cytotoxicity for more than two weeks.

    “Interestingly, it was shown that bsAb-retargeted PACTs can divide and secrete cytokines upon restimulation with target cells, while retaining their specificity and cytotoxicity for more than two weeks, which might be an important feature for therapeutic settings. 20”

    From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [20]

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Authors
Grabert, R. C., Cousens, L. P., Smith, J. A., Olson, S., Gall, J., Young, W. B., Davol, P. A., & Lum, L. G.
Affiliations
  • Roger Williams Medical Center (US)
  • Boston University (US)
  • University of California San Diego (US)
  • North Carolina State University (US)
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2006-01-15
Volume
12
Issue
2
Pages
569-576
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-05-2005
OpenAlex
W2149988468
Cited by
79
References
43
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 5 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 8 · 2013: 10 · 2012: 5
FWCI
1.39
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R01 CA 92334)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
bispecific antibodies, HER2/neu, HER2-positive breast cancer, T cell anergy, T cell division, cytotoxicity, perforin, cytokine production, interferon-gamma, RANTES, repetitive stimulation, adoptive T cell therapy, SK-BR-3 cells, cancer immunotherapy
MeSH terms
Breast Neoplasms, Cytotoxicity, Immunologic, Female, Humans, Immunotherapy, Interferon-gamma, Interleukin-2, Lymphocyte Activation, Membrane Glycoproteins, T-Lymphocytes, CD3 Complex, Antibodies, Bispecific, Erb-b2 Receptor Tyrosine Kinases, Chemokine CCL5, Cell Line, Tumor, Pore Forming Cytotoxic Proteins, Perforin

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