Yano Hiroshi, Thakur Archana, Tomaszewski Elyse N, Choi Minsig, Deol Abhinav, Lum Lawrence G
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.
J Transl Med. 2014 Jul 9;12:191. doi: 10.1186/1479-5876-12-191.
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).
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).
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.
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.
伊匹单抗是一种针对细胞毒性T淋巴细胞相关抗原4（CTLA-4）的拮抗单克隆抗体，通过抑制调节性T细胞（Treg）的免疫抑制活性来增强抗肿瘤免疫力。在本研究中，我们调查了在体外T细胞扩增过程中用伊匹单抗抑制Treg活性是否能增强抗CD3驱动的T细胞增殖，并增强双特异性抗体（BiAb）重定向的活化T细胞（ATC）的抗肿瘤细胞毒性。
来自健康个体的外周血单个核细胞（PBMC）用抗CD3单克隆抗体刺激，有或没有伊匹单抗，并扩增10-14天。收获ATC并用抗CD3×抗表皮生长因子受体（EGFR）双特异性抗体（EGFRBi）或抗CD3×抗CD20双特异性抗体（CD20Bi）进行武装，以测试针对COLO356/FG胰腺癌细胞系或伯基特淋巴瘤细胞系（Daudi）的重定向细胞毒性。
在来自健康个体的PBMC中，培养开始时添加伊匹单抗显著增强了T细胞增殖（p = 0.0029）。在伊匹单抗存在下培养的ATC在效应细胞：靶细胞（E:T）比例为25:1时，针对COLO356/FG和Daudi的平均肿瘤特异性细胞毒性分别显著增加37.71%（p < 0.0004）和27.5%（p < 0.0004），并增加了趋化因子（CCL2、CCL3、CCL4、CCL5、CXCL9和粒细胞-巨噬细胞集落刺激因子（GM-CSF））和细胞因子（IFN-γ、IL-2R、IL-12和IL-13）的分泌，同时减少IL-10分泌。
在伊匹单抗存在下扩增ATC不仅显著改善了T细胞增殖，还增强了细胞因子分泌以及双特异性抗体武装的T细胞的特异性细胞毒性。
