Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors

Area of Science:

• Immunology
• Virology
• Oncology

Background:

• Oncolytic viruses (OVs) expressing bispecific T-cell engagers (BiTEs) show promise in tumor immunotherapy but have limited tumor targeting.
• Effective T-cell stimulation is crucial for broad-applicability in cancer treatment.

Purpose of the Study:

• To develop and evaluate membrane-associated T-cell engagers (MATEs) for enhanced T-cell activation and broad tumor immunotherapy.
• To assess the efficacy of MATE-expressing OVs in reducing tumor growth and overcoming resistance to checkpoint therapy.

Main Methods:

• Established MATEs using the HIV-Tat protein transduction domain for non-selective binding.
• Utilized oncolytic adenovirus Ad5/11 to express MATEs in MC38 tumor models.
• Assessed T-cell activation, tumor killing, tumor growth, survival, and immune cell infiltration in vitro and in vivo.

Main Results:

• MATEs effectively activated murine and human T cells in vitro.
• MATE-expressing Ad5/11 reduced MC38 tumor growth, prolonged survival, and increased intratumoral CD8+ T cells in mice.
• MATE expression by Ad5/11 overcame resistance to αPD-1 checkpoint therapy.
• Absence of early T-cell activation in lymph nodes suggests safe applicability.

Conclusions:

• MATE-expressing OVs are potent tools for local tumor immunotherapy.
• This strategy facilitates broad T-cell activation and broad applicability against various tumors.
• MATE-expressing OVs can enhance the efficacy of existing cancer immunotherapies.