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Background <p>Cytotoxic T-cell-mediated tumor lysis is a key mechanism of oncolytic virotherapy. While oncolytic viruses expressing bispecific T-cell engagers (BiTE) enhance tumor targeting, they lack costimulatory signals, leading to T-cell exhaustion. We developed an oncolytic adenovirus expressing a trispecific T-cell engager (TriTE) to improve antitumor responses in colorectal carcinoma models.</p> Methods <p>An oncolytic adenovirus (Ad5-TriTE) was engineered to express a TriTE molecule targeting EpCAM (tumor antigen), CD3ε (T-cell activation), and 4-1BB (co-stimulation). For comparison, a BiTE-expressing virus (Ad5-BiTE) lacking 4-1BB was used. BiTE (αCD3ε-αEpCAM) facilitates T-cell redirection, whereas TriTE (αCD3ε-α4-1BBL-αEpCAM) adds co-stimulation for enhanced T-cell activation. Antitumor efficacy was evaluated in syngeneic and humanized colorectal carcinoma mouse models.</p> Results <p>Ad5-TriTE demonstrated efficient tumor infection and TriTE secretion, leading to superior tumor control compared to Ad5-BiTE. Enhanced CD8 + T-cell infiltration and activation correlated with improved antitumor effects in both subcutaneous and peritoneal metastasis models. The humanized version, Ad5-hTriTE, exhibited potent activity in a humanized colon cancer model.</p> Conclusions <p>Oncolytic adenovirus armed with TriTE enhances antitumor immunity by integrating costimulatory signaling. Incorporating costimulatory molecules into oncolytic virotherapy may offer more effective cancer immunotherapy strategies.</p>

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Enhancing oncolytic virotherapy with a tri-specific T-cell engager targeting CD3ε, EpCaM, and 4-1BB: preclinical evaluation and implications for cancer immunotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月30日

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  • Zhongyi Dong,
  • Haoyu Zhang,
  • Hailin Zhang,
  • Long Bai,
  • Qianyu Guo,
  • Guy Robinson,
  • Aya Elalfy,
  • Tao Liu,
  • Muerzhate Aimaiti,
  • Xiang Xia,
  • Shuguang Zuo,
  • Zizhen Zhang

摘要

Background

Cytotoxic T-cell-mediated tumor lysis is a key mechanism of oncolytic virotherapy. While oncolytic viruses expressing bispecific T-cell engagers (BiTE) enhance tumor targeting, they lack costimulatory signals, leading to T-cell exhaustion. We developed an oncolytic adenovirus expressing a trispecific T-cell engager (TriTE) to improve antitumor responses in colorectal carcinoma models.

Methods

An oncolytic adenovirus (Ad5-TriTE) was engineered to express a TriTE molecule targeting EpCAM (tumor antigen), CD3ε (T-cell activation), and 4-1BB (co-stimulation). For comparison, a BiTE-expressing virus (Ad5-BiTE) lacking 4-1BB was used. BiTE (αCD3ε-αEpCAM) facilitates T-cell redirection, whereas TriTE (αCD3ε-α4-1BBL-αEpCAM) adds co-stimulation for enhanced T-cell activation. Antitumor efficacy was evaluated in syngeneic and humanized colorectal carcinoma mouse models.

Results

Ad5-TriTE demonstrated efficient tumor infection and TriTE secretion, leading to superior tumor control compared to Ad5-BiTE. Enhanced CD8 + T-cell infiltration and activation correlated with improved antitumor effects in both subcutaneous and peritoneal metastasis models. The humanized version, Ad5-hTriTE, exhibited potent activity in a humanized colon cancer model.

Conclusions

Oncolytic adenovirus armed with TriTE enhances antitumor immunity by integrating costimulatory signaling. Incorporating costimulatory molecules into oncolytic virotherapy may offer more effective cancer immunotherapy strategies.