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Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing
Wen-Bin Zhao1, Ying Shen1, Guo-Xin Cai2
1National Key Laboratory of Advanced Drug Delivery and Release Systems & Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Zhejiang University Innovation Institute for Artificial Intelligence in Medicine, Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou 310018, China.
Abstract:
Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.
Insights
Novel superantigen-fused T cell engagers (TCEs) enhance T cell activation for improved solid tumor therapy. These engineered TCEs show potent and specific antitumor activity, offering a promising strategy for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- T cell engager (TCE) therapy efficacy is limited by inadequate T cell activation, particularly in solid tumors.
- Current strategies struggle to enhance T cell activity while preserving tumor specificity.
Purpose of the Study:
- To design and evaluate novel superantigen-fused TCEs for enhanced T cell activation and tumor-specific antitumor effects.
- To investigate the potential of these novel agents to overcome limitations in current TCE therapy.
Main Methods:
- Development of innovative superantigen-fused TCEs.
- In vitro and in vivo evaluation of antitumor activity and specificity.
- Assessment of T cell activation and chemotaxis signaling.
Main Results:
- Superantigen-fused TCEs demonstrated robust tumor antigen-mediated T cell activation.
- These novel agents exhibited significantly enhanced potency (>30-fold) and specificity (>25-fold) against tumors in vitro and in vivo.
- Induction of T cell chemotaxis signals was observed, suggesting improved T cell infiltration.
Conclusions:
- Superantigen-fused TCEs represent a promising strategy to improve the clinical efficacy of T cell engager therapy.
- The combination of superantigen potency and TCE specificity offers a dual advantage for cancer treatment.
- Potential for enhanced T cell infiltration may further boost therapeutic outcomes in solid tumors.
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