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Open Access Research

Ipilimumab augments antitumor activity of bispecific antibody-armed T cells

Hiroshi Yano1, Archana Thakur1, Elyse N Tomaszewski1, Minsig Choi1, Abhinav Deol1 and Lawrence G Lum123*

Author Affiliations

1 Departments of Oncology, Wayne State University and Barbara Ann Karmanos Cancer Institute, 740.1 Hudson Webber Cancer Research Center, 4100 John R., Detroit, MI 48201, USA

2 Medicine, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA

3 Immunology and Microbiology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA

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Journal of Translational Medicine 2014, 12:191  doi:10.1186/1479-5876-12-191

Published: 9 July 2014

Abstract

Background

Ipilimumab is an antagonistic monoclonal antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that enhances antitumor immunity by inhibiting immunosuppressive activity of regulatory T cells (Treg). In this study, we investigated whether inhibiting Treg activity with ipilimumab during ex vivo T cell expansion could augment anti-CD3-driven T cell proliferation and enhance bispecific antibody (BiAb)-redirected antitumor cytotoxicity of activated T cells (ATC).

Methods

PBMC from healthy individuals were stimulated with anti-CD3 monoclonal antibody with or without ipilimumab and expanded for 10-14 days. ATC were harvested and armed with anti-CD3 x anti-EGFR BiAb (EGFRBi) or anti-CD3 x anti-CD20 BiAb (CD20Bi) to test for redirected cytotoxicity against COLO356/FG pancreatic cancer cell line or Burkitt’s lymphoma cell line (Daudi).

Results

In PBMC from healthy individuals, the addition of ipilimumab at the initiation of culture significantly enhanced T cell proliferation (p = 0.0029). ATC grown in the presence of ipilimumab showed significantly increased mean tumor-specific cytotoxicity at effector:target (E:T) ratio of 25:1 directed at COLO356/FG and Daudi by 37.71% (p < 0.0004) and 27.5% (p < 0.0004), respectively, and increased the secretion of chemokines (CCL2, CCL3, CCL4,CCL5, CXCL9, and granulocyte-macrophage colony stimulating factor(GM-CSF)) and cytokines (IFN-γ, IL-2R, IL-12, and IL-13), while reducing IL-10 secretion.

Conclusions

Expansion of ATC in the presence of ipilimumab significantly improves not only the T cell proliferation but it also enhances cytokine secretion and the specific cytotoxicity of T cells armed with bispecific antibodies.

Keywords:
Ipilimumab; Cytotoxic T-lymphocyte antigen-4 (CTLA-4); Bispecific antibody; Pancreatic cancer; Colorectal cancer; Burkitt’s lymphoma; Activated T cells; Immunotherapy